Ted Maher, 44, a former Green Beret who was employed as one of Safra's nurses, looked pale when he entered the courtroom packed with journalists and witnesses but closed to the public.
Maher has been held in Monaco's tiny waterfront jail since Safra's death in December 1999, when he allegedly confessed to setting fire to the ailing banker's heavily fortified penthouse in a botched bid to prove himself a hero.
Prosecutors say Maher who faces life in prison if convicted started the blaze but then raised the alarm and stabbed himself with a knife to make it look as if a gang had raided the flat.
But Safra and another of his nurses, 52-year-old Vivian Torrente, sought refuge in the bathroom. Safra refused to leave out of fear and the two died of smoke inhalation in the ensuing confusion.
The banker, a Lebanese Jew who founded the Republic National Bank of New York, left most of his multi-billion-dollar fortune to his widow Lily, a high-society hostess who splits her time between New York and London.
Her fame in the celebrity pages, allegations of a bitter row between her and Safra's brothers, and unsubstantiated rumours of a cover-up have all heightened international interest in the trial.
Arriving at the Monaco courthouse, Lily Safra nicknamed "The Gilded Lily" avoided the 80 international reporters and photographers by entering through a side door.
Maher was hired by Safra earlier in 1999 but was unhappy because he felt his expertise was overlooked by senior members of the banker's nursing staff, prosecutors say.
But Maher's attorneys insist that he never intended to kill Safra and that the banker's death is instead due to negligence on the part of the police and fire services, who they say should have been able to save the two victims.
"It should be very interesting today. I'm very confident and there will be surprises and interesting testimonies," said Michael Griffith, Maher's US attorney.
Several questions remain unanswered, such as why Safra would have dispensed with his team of Mossad-trained bodyguards that day, and why their chief, who had a key to the apartment, was denied access by police surrounding the building during the fire.
Rumours also spoke of two bullet wounds in Safra's body and of a recent feud with the Riviera's Russian mafia.
Prosecutors say Maher confessed to the fire and to the self-inflicted wounds while being treated in hospital, but his lawyers plan to argue that. Maher will be helped by an interpreter during the trial.
Lily Safra married Edmond in 1976, bringing with her a multi-million-dollar fortune inherited from her second husband who died in suspicious circumstances.