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In Paris in 1890, as crowds pour into the Moulin Rouge nightclub, young artist Henri de Toulouse-Lautrec finishes a bottle of cognac and sketches the dancers as they perform.  The nightclub's regulars each stop by: 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 body.  As he walks to his Montmartre apartment, he recalls the events that led to his disfigurement.

Henri is a bright, happy child, revered by his father, the Count de Toulouse-Lautrec.  When he falls down a flight of stairs, however, his legs fail to heal, a genetic weakness that stems from the fact that his parents are first cousins.  His legs stunted and pained, Henri loses himself in his art, while his father soon leaves the countess to ensure they will have no more children.

As a young adult, Henri proposes to the woman he loves but, when she tells him 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 guardian, after which she insists on following him home.  There, she addresses his small stature, and although he is at first angry, he allows her to stay out of his desperate loneliness, and is charmed when she claims not to care about his legs.

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, tells her to leave at once.  Realizing that he loves her, she vows to stay and love him back.  Although she continues to fight petulantly with him, he tells himself that her crassness stems from her poverty, and lets her stay.  During one fight, however, she announces that he can never attract a real woman, and leaves.  By morning, she begs him to take her back, but he refuses.

He begins drinking and does not stop until his landlady calls his mother, who urges him to save his health by finding Marie.  He searches her working-class neighborhood, finally discovering her at a café, where she drunkenly reveals that she stayed with him only to procure money for her boyfriend.  When she adds that his touch made her sick, he 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, distractedly turns the vents off again.

The next day, he brings the poster to the dance hall, and although 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 legs exposed, becomes an instant sensation and the dance hall opens to high society.  The Count, however, denounces Henri for the "pornographic" work.

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Over the next ten years, Henri records Parisian life in countless brilliant paintings.  By 1900, he is famous but still terribly lonely.  One day, he sees Myriamme Hyam standing by the Seine River and, thinking she may jump, stops to talk to her.  She spurns his advances and throws a key into the water.  Days later, Jane, a friend of Myriamme's, arranges a meeting for them.  Myriamme is a great admirer of Henri's paintings, and the two begin to spend time together.  Eventually, she reveals that the key she threw out belonged to a married man, Marne de la Voisier, who asked her to be his mistress.  Although Henri continues to decry the possibility of true love, he nonetheless falls in love with Myriamme.

One day, they see La Goulue on the street drunkenly insisting that she was once a star, and Henri realizes that once the Moulin Rouge became respectable, it could no longer be home to misfits.  Myriamme later informs Henri that Marne has asked her to marry him.  Certain that she loves the more handsome man, he bitingly congratulates her for trapping Marne.  Even after she asks if he loves her, Henri believes she is only trying to spare his feelings and lies that he does not.  By the time he receives a letter stating that she loves him but cannot wait any longer, she has already left the city and he cannot find her.

Weeks later, he is still drinking steadily and reading her note over and over.  He is helped home one night by Patou, now an inspector, but once home, Henri hallucinates and throws himself down a flight of stairs.  Near death, he is brought to his family home.  After the priest reads the last rites, the Count tearfully informs Henri that he is to be the first living artist to be shown in the Louvre, and begs for forgiveness.  Henri turns his head and watches as phantasmal characters from his Moulin Rouge paintings dance into the room to bid him goodbye.