Britain's Geraint Thomas is out of contention for the Giro d'Italia after losing more than 12 minutes on stage three to Mount Etna.
The Ineos Grenadiers rider, 34, crashed just before the start after a drinks bottle became lodged under his front wheel.
Fellow Briton and race favourite Simon Yates of Michelton-Scott lost more than four minutes.
The stage was won by EF Pro Cycling's Jonathan Caicedo.
Deceuninck-Quick Step's Joao Almeida now wears the leader's pink jersey, although he is tied on time with Caicedo.
What happened to Thomas and Yates?
Thomas - Tour de France champion in 2018 - and Yates were the two strongest contenders to win this year's Giro, which promised to be a battle of two riders coming into form.
Instead, it was a miserable day for both as the rain fell in the dramatic surrounds of Etna's dried black lava flows.
Welshman Thomas crashed during the neutralised zone before the start of the mountainous stage up to Sicily's volcano.
He appeared to be riding comfortably despite badly torn kit and landing on his hip.
But Thomas slipped back from the peloton about 25km from the end of the stage.
Ineos even sacrificed the leader's pink jersey, taking race leader Filippo Ganna back to try to help Thomas recover.
Thomas was third in the general classification before the stage, 26 seconds ahead of Yates in eighth.
Soon after Thomas' demise, Yates began to fade in a similar way, slipping back from a rapid peloton.
Yates had shown strong form in the lead-up to the Giro, winning last month's Tirreno-Adriatico warm-up race a few seconds ahead of Thomas, who was also recovering form after being left out of the Tour de France.
With 18 days of racing remaining, Thomas is 11 minutes 17 seconds down in the general classification, while Yates has a deficit of 3mins 46secs.
It will be a bitter disappointment for Ineos, who had a terrible Tour campaign by their standards after defending champion Egan Bernal abandoned the race when he lost seven minutes to leaders on stage 15. The team had won every Tour since 2015 until last month.
Thomas will be assessed by the team's medical staff and a decision made on whether he should continue in the race from Tuesday's 140km sprint stage from Catania to Villafranca Tirrena.
Ineos may chose to focus their general classification aims on Tao Geoghegan Hart, who is their highest-placed rider at 3mins 19secs off the lead.
The highest-placed British rider is Deceuninck-Quick Step's James Knox, at 1min 40secs behind.
"It's still a long Giro," said Ineos sport director Matteo Tosatto. "We have Filippo and Rohan [Dennis] with some good chances in the time trials and we also have [Jonathan] Castro[viejo] and Tao riding well. We'll take stock tonight and look at our approach for the rest of the race."
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The Shark smells blood
As rivals sensed trouble for both riders the pace of the peloton picked up, with two-time winner Vincenzo Nibali's Trek-Segafredo team taking over at the front.
Despite a stray Labrador nearly knocking several riders off their bikes before the final 19km climb up to Etna, many of the remaining team leaders made back time.
Steven Kruijswijk of Jumbo-Visma, Astana's Jakob Fuglsang, Bora-Hansgrohe's Rafal Majka and Nibali - nicknamed the Shark of Messina - all recovered time lost after poor time trials on stage one.
Sicilian Nibali, 35, is now one of the favourites at 55 seconds behind Almeida.
Stage 3 result
1. Jonathan Caicedo (Ecu/EF Pro Cycling) 4 hours 02 minutes 33 seconds
2. Giovanni Visconti (Ita/Vini Zabu-KTM) +21secs
3. Harm Vanhoucke (Bel/Lotto-Soudal) +30secs
4. Wilco Keldermann (Ned/Sunweb) +39secs
5. Jakob Fuglsang (Den/Astana) +51secs
6. Rafal Majka (Pol/Bora-Hansgrohe) same time
7. Vincenzo Nibali (Ita/Trek-Segafedo) same time
8. Jonathan Castroviejo (Spa/Ineos Grenadiers) same time
9. Domenico Pozzovivo (Ita/NTT) same time
10. Steven Kruijswijk (Ned/Jumbo-Visma) +56secs
31. Simon Yates (GB/Michelton-Scott) +4mins 22secs
69. Geraint Thomas (GB/Ineos Grenadiers) +12mins 19secs
1. Joao Almeida (Por/Deceuninck-Quick Step) 7 hours 44 minutes 25 seconds
2. Jonathan Caicedo (Ecu/EF Pro Cycling) same time
3. Pello Bilbao (Spa/Bahrain-McLaren) +37secs
4. Wilco Keldermann (Ned/Sunweb) +42secs
5. Harm Vanhoucke (Bel/Lotto-Soudal) +53secs
6. Vincenzo Nibali (Ita/Trek-Segafedo) +55secs
7. Domenico Pozzovivo (Ita/NTT) +59secs
8. Brandon McNulty (USA/UAE-Team Emirates) +1min 11secs
9. Jakob Fuglsang (Den/Astana) +1min 13secs
10. Steven Kruijswijk (Ned/Jumbo-Visma) +1min 15secs
25. Simon Yates (GB/Michelton-Scott) +3mins 46secs
53. Geraint Thomas (GB/Ineos Grenadiers) +11mins 17secs