The Slovakian was reported to have felt ill after Tuesday's second stage, where he finished fourth in the sprint after 219 kilometres of racing. Wednesday morning brought a bout of vomiting for the former world champion.
Cyclingnews' reporter on the ground in Italy Stephen Farrand confirmed that Sagan is out of the race suffering from a fever in addition to his stomach problems.
The illness is the latest setback for Sagan after an unlucky start to his TotalEnergies tenure. His early season training was compromised after he caught COVID-19 for a second time in early January, while he looked off the pace at Omloop Het Nieuwsblad and Kuurne-Brussel-Kuurne last month.
Sagan was suffering from a sore throat and a fever last week, though he tested negative for COVID-19. It's unknown whether his current illness is a continuation of that or a new infection.
The 32 -year-old seemed to bounce back with his fourth place finish on Tuesday, and he'll now turn his attention to his first major goal of the season at Milan-San Remo in 10 days' time, with Milano-Torino (March 16) also on his calendar.
However, his absence from the remainder of Tirreno-Adriatico will mean that he's set to miss out on valuable racing preparation days for La Classicissima.
Sagan was in competition for the in Sovicille on Tuesday after his TotalEnergies lead out hit the front in the final kilometres of the stage.
He hit the front after launching his sprint, but faded during the dash to the line, and was passed by eventual winner Tim Merlier (Alpecin-Fenix) in the closing metres. Young sprinters Olav Kooij (Jumbo-Visma) and Kaden Groves (BikeExchange-Jayco) also went past to take second and third.
"What can I say? It could have gone better but it could have gone worse," Sagan said, after the finish.
"They came up and over me from behind really strongly and with speed, and that made the difference."
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Daniel Ostanek is production editor at Cyclingnews, having joined in 2017 as a freelance contributor and later being hired as staff writer. Before Cyclingnews, he was published in numerous publications around the cycling world, including Procycling, CyclingWeekly, CyclingTips, Cyclist, and Rouleur, among others. As well as reporting and writing news and features, Daniel runs the 'How to watch' content throughout the season.
Daniel has reported from the world's top races, including the Tour de France, and has interviewed a number of the sport's biggest stars, including Egan Bernal, Wout van Aert, Remco Evenepoel, Mark Cavendish, and Anna van der Breggen. Daniel rides a 2002 Landbouwkrediet Colnago C40 and his favourite races are Strade Bianche and the Vuelta a España.