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In the 1920s, in Bruges, Brussels, Gabrielle Van der Mal is preparing to be a nun.  She leaves behind her worldly goods, but decides to keep a pen given to her by her widowed father, a renowned physician.  After bidding farewell to her sisters and brother, Gaby walks with her father to the convent.  Dr. Van der Mal doubts that Gaby is meant to be a nun, saying that he can see her chaste and poor, but never obedient.  After reminding her that the Order forbids her to ask for her most heartfelt desire, which is to be assigned to the Congo as a nurse, he tells her not to believe she has failed if she is ill-suited to convent life.  Feeling certain of her vocation, Gaby serenely dismisses his misgivings.

At the convent, her father points out a nun who is considered a "Living Rule," because she personifies the rules of the Order by her exemplary behavior.  After presenting Gaby’s dowry to the Order, Dr. Van der Mal tells his daughter to be happy and leaves.  Gaby is disappointed to learn that she is forbidden to talk to her mentor, the nurse Sister William, for many months.  Following strict rules, the postulants adapt to the sound of the bells, which call them to awaken, to chapel, to meals and to the Grand Silence, which are the hours the nuns are forbidden to talk.  To develop their spiritual life, the postulants may not ask for anything on their own behalf and are strenuously tested to root out their faults.  Mother Emmanuel tells them that the self-sacrificing life of a nun is a life against nature.

On their Day of Vesture, when they are given new names and the novice’s habit, the young women are expected to turn from memories of their past, requiring that Gaby give up the pen from her father.  Henceforth, she is known as Sister Luke.  After the ceremony, Gaby blushes when her hospital patients tell her she is "a beautiful nun," and thus commits the sin of pride.  By discussing her discomfort with a fellow novice, she breaks the rule of silence.  New tests and penances are introduced to the novices and, once a week, they are expected to announce publicly their own faults, as well as those of others they have witnessed.  Although she tries to obey, Gaby frequently breaks rules and, even when she succeeds in following the rules, feels she is sinning by taking pride in her success.

After taking her vows, Gaby is sent to the School of Tropical Medicine in Antwerp.  Having already been trained by her father, Gaby does well, but incites the jealousy of an older nun, who reports to Mother Marcella that Gaby is guilty of pride.  Marcella suggests to Gaby that she fail her examinations to prove her humility, but soul-searching prevents Gaby from doing so.  Afterward, instead of sending Gaby to the Congo, Marcella assigns her to work in a mental sanitarium.  There, a dangerous schizophrenic patient nicknamed Archangel tricks Gaby into unlocking her cell without asking for assistance.  After Archangel attacks her, the shamed Gaby chides herself for her prideful belief that she could handle the situation alone and confides to the sanitarium’s Mother Superior of her internal struggle with obedience.  The nun, believing Marcella was wrong to ask Gaby to fail intentionally, suggests that she be easier on herself.

After three years, Gaby takes final vows, as her family watches the ceremony.  Although she is assigned to the Congo, Gaby is disappointed to learn that she will not work with the natives, but at the "white" hospital for Europeans under the supervision of the eccentric Dr. Fortunati, a bachelor and atheist described as a "genius and devil" by the nuns.  The shrewd and demanding Fortunati is pleased with Gaby’s professionalism, but discerns her exhausting inner struggle.  Gaby works long hours and institutes useful innovations, only to be accused by the bishop of "singularizing" herself when her successes draw attention.  When a beloved priest has an accident possibly requiring amputation and there are no doctors available to treat him, Gaby saves the priest and his leg, garnering praise from Fortunati, who then jokes that she will have to confess her "sin of pride."  Later, with Fortunati, Gaby visits a leper colony served by a priest, who has dedicated himself to the lepers as a penance for past sins and is now infected himself.

Back at the hospital, Gaby's nursing duties conflict with her religious obligations.  Although her obligations to her religious life are supposed to take precedence, Gaby cannot sacrifice her patients’ psychological needs to the Grand Silence.  As Fortunati feared, Gaby’s tension from her inner struggles combined with long hours of work take their toll and she contracts tuberculosis, a disease for which she would be required to leave the Congo.  Having worked with many nursing nuns, Fortunati tells Gaby that she is a "worldly nun," who is good for patients, but who cannot conform to the convent’s expectations.  "That’s your illness," he says, "the TB is a byproduct."  After he wryly warns her not to let the sin of pride make her confess that she correctly diagnosed her illness, he promises to cure the "byproduct" and explain it to the Mother Superior in a way that allows Gaby to remain.

He prescribes several months of rest in isolation, where Gaby is pampered with wine and a special diet, and given a pet monkey.  As she recuperates, she is at peace with herself and jokes to a fellow nun that she may never again break a rule.  Wryly, the nun tells her they are talking during Grand Silence.  After she returns to duty, a native man, swayed by a witch doctor’s superstitions, kills a kindly nun who hoped to convince unconverted natives to attend Christmas Eve service.  Illunga, a native who assists the nuns, confides to Gaby his surprise that the nuns are not angry.  After Gaby explains the nuns’ belief in forgiveness, Illunga and others come to the service.  When a nurse is needed to accompany an important mental patient to Belgium, Gaby is the only person suitably trained.  She fervently hopes that she will be allowed to return, but the Mother Superior decides to keep her there as "a good example" to the other nuns while she renews her spiritual life.

From her father, who continues to worry that her life is being misspent, Gaby learns that her brother and two brothers-in-law are in the army.  After Fortunati writes that her replacement "is a real nun," the Mother Superior asks Gaby if she was in love with the doctor, but Gaby denies it.  Although she prays for detachment from her memories, Gaby remembers Fortunati’s prediction that she would be unhappy at the motherhouse.

The outbreak of World War II makes Gaby’s return to the Congo impossible.  German bombing is followed by the German occupation of Belgium, but the nuns are expected to feel charity toward their enemy.  In the local hospital where she is assigned, Gaby observes that a young nurse, the novice Lisa, is helping the Underground Resistance.  After asking God to forgive her disobedience, Gaby offers her help.  Upon learning that her father has been killed, Gaby wrestles with her conscience, finally acknowledging that she is "filled with hate."  Believing that she should no longer be a nun, Gaby asks for permission to leave the convent.  When permission is denied, she threatens to leave without it.  Lisa, who guesses Gaby’s decision, gives her a contact in the Underground, so that she has a place to go where her skills can be used.  After convincing her superiors to put through her paperwork, Gaby is called in to sign the documents and her dowry is returned, but she is refused a last blessing by the Mother Superior.  Alone, she is sent to a room, where she replaces her habit with civilian clothes and takes off the wedding ring that symbolizes her marriage to Christ.  After exiting the convent, she walks away to a different life.