In 1890 Paris crowds pour into the Moulin Rouge nightclub as artist Henri de Toulouse-Lautrec finishes a bottle of cognac while sketching the club's dancers. The club's regulars arrive: singer Jane Avril teases Henri charmingly, dancers La Goulue and Aicha fight, and owner Maurice Joyant offers Henri free drinks for a month in exchange for painting a promotional poster. At closing time, Henri waits for the crowds to disperse before standing to reveal his four-foot six-inch stature. As he walks to his Montmartre apartment, he recalls the events that led to his disfigurement.
In flashbacks it is revealed that Henri was a bright, happy child, cherished by his parents, the fabulously wealthy Count and Countess de Toulouse-Lautrec. But as a boy Lautrec fell down a flight of stairs and his legs failed to heal because of a genetic weakness, likely resulting from his parents being first cousins. His legs stunted and pained, Henri loses himself in his art, while his father leaves his mother to ensure that they have no more children. As a young adult, Henri proposes to the woman he loves but, when she tells him that no woman will ever love him, he leaves his childhood home in despair to begin a new life as a painter in Paris.
Back in the present, street walker Marie Charlet begs Henri to rescue her from police sergeant Patou. Henri wards off the policeman by pretending to be her escort, after which she insists on following him home. There, she acknowledges his disability with complete dispassion and although he is at first angry, Lautrec is impressed by her lack of judgement of his condition. He allows her to stay and comes to realize that the poverty and brutality of her childhood have made her cruel, ignorant and sly but also free of society's hypocrisy. Within days, he is buying her gifts and singing as he paints, until Marie takes his money and stays out all night.
Henri waits in agony for her return, but when she finally does he tells her to leave at once. Realizing he loves her, Marie vows to stay and love him back. Although they fight constantly and he knows he can't trust her, Henri is unable to break with her. A final battle breaks out when Marie demands to be paid for posing for a portrait and flies into a rage when she thinks the portrait is unflattering. By morning, she begs him to take her back, but he refuses. He begins drinking himself to death until his landlady calls his mother, who urges him to save his health by finding Marie.
Henri searches Marie's working-class neighborhood, finally discovering her at a café, blind drunk and sobbing. Marie reveals that she stayed with him only to procure money for her boyfriend, who has dumped her. When she adds that his touch made her sick, Henri returns to his apartment, and turns on the gas vents. As he sits waiting to die, he is suddenly inspired to finish his Moulin Rouge poster and, brush in hand, turns the gas vents off and opens the windows. Having passed through the crisis, he asks Sergeant Patou to secretly give Marie enough money to lift her out of her abject misery.
The next day, Henri brings the poster to the dance hall and, though the style is unusual, Maurice accepts it. Henri works for days at the lithographers, blending his own inks to perfect the vivid colors. When he finishes the poster, which shows a woman dancing with her frilly panties exposed, it becomes an instant sensation and the Moulin Rouge opens to high society. His father denounces Henri for the "pornographic" work. Over the next ten years, Henri records the Parisian demimonde in brilliant paintings. His irascibility causes him to fight constantly with other painters but his broker loyally fights for his art to be accepted. By 1900 he is famous, but still terribly lonely.
One morning he sees an elegant young woman standing at the edge of Pont Alexandre III over the Seine River. Thinking she might be suicidal, he stops to talk to her. She tells him she isn't going to jump and throws a key into the water. Days later, Jane Avril goes shopping with Henri, where the young woman is modeling gowns at a dress shop. She is Myriamme, Jane's friend who, unlike Jane, lives on her own earnings and not the patronage of rich lovers. Myriamme is a great admirer of Henri's paintings, and Henri is shocked to discover that she bought the portrait of Marie Charlet years before in a flea market.
Myriamme is Marie's opposite: principled, kind and cultured. She reveals to Henri that the key she threw into the water belonged to a wealthy and dashing man, Marcel de la Voisier, who asked her to be his mistress, but not his wife. While Henri continues to bitterly decry the possibility of true love, he falls in love with Myriamme. One night the two see dancer La Goulue on the street drunkenly insisting that she was once a star. Henri realizes that the Moulin Rouge has become a respectable establishment and is no longer the home for misfits.
Myriamme informs Henri that Marcel has finally asked her to marry him. Certain she loves the more handsome man, he bitingly congratulates her for trapping Marcel. Myriamme asks Henri if he loves her, but, believing that she is only trying to spare his feelings, he lies and tells her he does not. The next day Henri receives a letter from Myriamme telling him that she loves him, not Marcel, but she believes Henri's bitterness over Marie has poisoned any chance for them to be happy together. Rushing to Myriamme's apartment, Henri finds she has left to marry Marcel. Weeks later, while sitting in a sleazy dive drinking relentlessly, Henri obsessively reads Myriamme's note. Patou, now an inspector, is called to help him. Once home, in a state of delirium tremens, Henri hallucinates that he sees cockroaches, and in trying to drive them away, accidentally falls down a flight of stairs.
Near death, Henri is brought to his family's chateau. After a priest reads the last rites, his father tearfully informs Henri that he is to be the first living artist to be shown in the Louvre, and begs for forgiveness. Dying, Henri turns his head and smiles as phantasmal characters from his Moulin Rouge paintings, including Jane Avril, dance into the room to bid him goodbye.
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