Australia's Jai Hindley, runner-up in last year's Giro d'Italia, was forced to pull out of this year's race before Saturday's mountainous 14th stage to the fearsome Monte Zoncolan.
His Team DSM revealed the 25-year-old rider had "suffered intensely with a serious saddle sore that has prevented him from riding his best over the last week.
"The 2020 runner up is no longer fit to race, and will instead head home to recover."
"This is obviously not how I wanted my Giro to end," said Hindley.
"The team have really put in a lot to try and help, but the situation isn’t improving and I really can’t continue anymore."
Hindley was 25th in the overall standings.
"Jai has been suffering pretty hard over the last few days with a saddle sore," said team doctor Anko Boelens.
"We had hoped things would improve, but his condition has deteriorated significantly after the stage yesterday.
"His pain levels are no longer tolerable and with some huge days in the mountains coming up, he cannot continue the race like this."
The Jumbo team's Dutch riders Dylan Groenewegen and David Dekker also both pulled out of the race before the mountains.
"The reservoir is empty for them," said team sporting director Arthur van Dongen.
Colombian Egan Bernal of Ineos wears the pink jersey in the 14th stage over 205km from the medieval walled town of Cittadella, in the province of Padua, to Monte Zoncolan in the Carnic Alps.
Zoncolan is one of the toughest climbs in Europe, featuring a final kilometre with a 14.7 percent gradient to the finish line complicated by forecasts of rainy and cold conditions.