Claudio Ranieri resigned as coach of AS Roma following their shock 4-3 loss at Genoa on Sunday in a game they had led 3-0.
"I have always thought about the good of Roma," he was quoted as saying by ANSA news service.
"After a game like that today, I think it is right to give a signal. At the final whistle I went into the dressing room to thank the team and I have decided to resign."
Cash-strapped Roma, who are in the process of being sold, lost 3-2 at home to Ukrainians Shakhtar Donetsk in the Champions league last-16 first leg on Wednesday.
Around 200 fans protested at Roma's training ground on Saturday, throwing flares and firecrackers at the gates before being dispersed by police.
Roma produced a stunning run to finish second in Serie A last term in Ranieri's first season in charge after taking over from Luciano Spalletti. They now lie eighth.
American consortium Di Benedetto is in exclusive talks to buy the club and media reports had said they might look to replace the former Valencia and Juventus coach in any case with Chelsea boss and Roma fan Carlo Ancelotti touted.
Retired former Roma striker Vincenzo Montella is being mentioned in the media as potential a caretaker.
Rome-born Ranieri has also had a difficult relationship with club captain Francesco Totti, who has played for Roma his whole career and is regarded by fans as the heartbeat of the club.