Alberto Contador suffered a broken leg and crashed out of the Tour de France on Monday as Vincenzo Nibali took full advantage with a scintillating victory at La Planche des Belles Filles which saw him reclaim the yellow jersey.
Two-time winner Contador crashed on the 161.5-kilometre 10th stage from Mulhouse and, after struggling on for 20km in an effort to play catch-up, gave up and withdrew to his Tinkoff-Saxo team car.
Tour organisers confirmed Contador sustained a fractured tibia (shin bone) in a statement on letour.com.
It read: "Alberto Contador suffered a shin bone fracture after his crash 95km from the finish of stage 10 between Mulhouse and La Planche des Belles Filles."
The Spaniard's departure deprives the race of another previous winner after 2013 champion Chris Froome (Team Sky) withdrew with fractures to his left wrist and right hand on stage five last Wednesday.
Andy Schleck (Trek Factory Racing), who inherited the 2010 title from Contador following an anti-doping infringement, quit the race with a knee injury last Tuesday, although the Luxembourg rider is a shadow of his former self.
None of the remaining riders have won the event, but Nibali took a significant step in his bid to succeed Froome as champion in Paris on July 27.
The action was expected to ignite on the concluding climb ahead of Tuesday's rest day and Nibali, who relinquished the lead on stage nine to Frenchman Tony Gallopin (Lotto-Belisol), surged to a second Tour stage win to take control of the race.
Nibali holds a lead of 2:23 from second-placed Richie Porte (Team Sky), who was 25 seconds behind in seventh on the day.
Alejandro Valverde (Movistar) is third, 2:47 behind.
Nibali's advantage is so commanding that three-time champion Greg LeMond believes it is unlikely the Italian will be beaten.
"Personally I don't think there's much of a challenge any more," LeMond told British Eurosport.
"If he does have a bad day, I think it's the only time anyone has a chance. I think it's wishful thinking, but it could happen."
Nibali refuses to take his lead for granted, knowing he too could crash out and that Porte and Valverde are lurking.
"This is a wonderful victory," Nibali said on letour.com.
"This was the hardest stage I've ever done in a Grand Tour, with seven climbs and so many crashes.
"I feel sorry for Alberto Contador. He crashed just in front of me and I've been scared that I'd go down as well but I don't know why he crashed.
"I'll try to keep the yellow jersey but I won't be left without rivals. Richie Porte and Alejandro Valverde are up there.
"I'll have to handle my advantage."
The race heads towards the Alps on its resumption on Wednesday with the 187.5km 11th stage from Besancon to Oyonnax, but without Contador as the Tour lost another leading protagonist following Mark Cavendish's crash on day one and the exits of Froome and Schleck.
Contador, the 2007 and 2009 winner, crashed on the descent of the Petit Ballon as he approached the third of seven categorised climbs, the Col du Platzerwasel, on a damp day in the Vosges Mountains.
He received strapping to his right knee, swapped bikes and lost four minutes as a result of the delay, falling nine minutes behind the day's breakaway, which held a five-minute lead on the peloton.
Nibali's Astana team led the main bunch and waited, but it soon became apparent Contador would not be returning and the pursuit of the day's breakaway resumed in earnest.
Contador's withdrawal could see him refocus on the Vuelta a Espana, which begins in Jerez on August 23. It could be Froome and Sir Bradley Wiggins also ride the Tour of Spain.
Froome wrote on Twitter: "Big loss for the TDF today. Recover well @albertocontador & I hope to see you at the Vuelta."
The finish at La Planche des Belles Filles was a reminder to Britons of the absent Froome and Wiggins.
Froome won at the summit of the 'climb of the beautiful girls' in 2012 as Wiggins took the yellow jersey he held until Paris, when he became the first British winner of the race.
Nibali finished third two years ago, won the 2013 Giro d'Italia and took a major step towards Tour victory by attacking with 3km to go.
He surged past Joaquim Rodriguez (Katusha), the last of the day's breakaway riders, as Porte tried to follow.
Thibaut Pinot (FDJ) was 15 seconds behind in second and Valverde third.
Porte told ITV4: "I think I was the only one that responded (to Nibali's attack).
"Vincenzo goes you have to respond. He's got enough time already so you don't really want him to get any more.
"It's a shame to lose Alberto like that. I think it's definitely going to change the dynamics of the race.
"I think it probably would've been a harder finale had Saxo been there."
On his overall chances, the Australian added: "We'll take it day by day. I think we're in a pretty good position going into the first rest day."