The Australian climbed off his bike with around 100km to go on the stage that was won by Mathieu van der Poel in an uphill sprint.
His team later stated he had 'mild gastro-enteritis' and his abandon was more of a precaution ahead of one of his major goals.
"Caleb Ewan has withdrawn from the race as he has been suffering from mild gastro-enteretis," said the team. "The decision to abandon was taken in order to not jeopardise his participation at Milan-San Remo this coming Saturday."
Ewan came into Tirreno-Adriatico after starting his season at the UAE Tour where, despite not feeling happy with his performances, he took home a stage win.
He was considered the favourite for the flat bunch sprint on the opening day of Tirreno but was beaten to the line by Wout Van Aert (Jumbo-Visma).
He finished 164th and 15 minutes down on stage 2, before leaving the race on stage 3.
Ewan will now rest up before completing his final preparations for next weekend's Milan-San Remo, where he was runner-up in 2018. He'll lead the line for Lotto Soudal alongside Philippe Gilbert, who's looking to complete the collection of five Monuments.
The rest of Ewan's season is set to involve visits to the Giro d'Italia, Tour de France, and Vuelta a España. The 26-year-old has won stages at all three races in the past but is aiming to become the first rider since Alessandro Petacchi in 2003 to do so in the same calendar year.
Thank you for signing up to Cycling News. You will receive a verification email shortly.
There was a problem. Please refresh the page and try again.