World champion Michal Kwiatkowski and Tejay Van Garderen pulled out of the Tour de France during Wednesday`s 161km 17th stage from Digne-les-Bains to Pra Loup.
Pole Kwiatkowski, 25, had been struggling earlier in the stage and inside the final 35km the news came confirming the Etixx-Quick Step rider was out.
American Van Garderen had been sitting third in the overall standings at 3min 32sec back from race leader Chris Froome.
But only 60km into the first Alpine stage of the race, Van Garderen started to struggle and lost touch with the peloton.
The 26-year-old BMC team leader, who was second to Froome in last month`s Criterium du Dauphine, was suffering from headaches.
He dropped two minutes behind but his teammates helped him back up to the peloton, only for an acceleration from Alberto Contador, who was fifth overall, to see Van Garderen dropped again and, with 70km still to ride, he climbed off his bike.
It means Spaniard Alejandro Valverde moves up into a podium position behind second-placed Nairo Quintana with Contador just 19sec behind.