The husband, Dominique Pelicot, offered sex with his wife on a website, and filmed the abuse, the prosecutor's office said. Fifty other men accused of raping his wife when she was knocked unconscious by the drugs are also on trial.
They each face up to 20 years in jail if found guilty.
Due to the drugs, Pelicot's wife had been entirely unaware of the rapes, which took place at their home in the southern French town of Mazan, until police told her about them four years ago, her lawyers have said.
"She knew nothing of what was inflicted on her. She had no memory of the rapes she suffered," lawyer Antoine Camus told France Bleu radio.
French media including Le Monde have said that police stumbled upon Pelicot's thousands of pictures and video of his wife's abuse when investigating him after several women said he was using his phone to film under their skirts in a supermarket.
The men were of all ages and all walks of life, French media said, adding that some admitted to being guilty while others said they thought the wife had pretended to be asleep.
The trial, which is set to include video footage of the rapes, will be a "terrible ordeal" for her, Camus said.
The trial opened on Monday and is set to last until December and will not be held behind closed doors as is common in cases of violent sex crimes.
Pelicot's wife, now aged 72, said she wanted it to be held publicly to alert the public to sexual abuse and drug-induced blackouts, her lawyers said.
Lawyer Stephane Babonneau, who also represents the victim, told French media she wanted to show "that shame must change sides".
Beatrice Zavarro, a lawyer for Dominique Pelicot, has told French media he admits to his crimes.
