Jumbo-Visma announced that the Dutchman fell ill on the rest day and did not recover in time to resume the race.
A tweet from his team said Kruijswijk will now turn his attention to the Vuelta a Espana, with the 21-stage course starting on August 14.
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Kruijswijk becomes the 40th rider to leave the lap, with 144 remaining to compete in the last five stages.
The 34-year-old’s forced departure exacerbates his squad’s misery, with Kruijswijk becoming the fourth Jumbo-Visma rider to drop out of the tour.
Robert Gesink, Tony Martin and Primoc Roglic all left the circuit, leaving Jumbo-Visa with just four riders to fight for a podium.
Roglič’s downfall and his subsequent retirement were a particularly hard blow given that the Slovenian had been chosen to lead the Dutch team.
Roglič’s replacement as leader, Jonas Vingegaard, now represents the team’s best chance to reach the podium.
Vingegaard is currently in third place after a strong opening weekend.
The other three remaining riders from Jumbo-Visma are Wout van Aert, Sepp Kuss and Mike Teunissen.
Stage 16 saw a victory for Patrick Konrad as the Austrian claimed his first stage victory on the Tour de France.
The 29-year-old went on the attack with a climb to go to the Col de Portet-d’Aspect and claim victory.
Tadej Pogacar retains the yellow jersey heading into the final five stages as the 22-year-old looks to defend his title.
Despite his lead, the Slovenian told reporters he was anticipating his toughest challenge yet ahead of Stage 17, a summit race to the summit of Col du Portet.
He said, “It’s going to be a big battle. It’s going to be hard. “
There was no profile for large GC deviations. So tomorrow everyone will try, because it’s the hardest day of the Tour. I did a recce for tomorrow and the day after so I know the climbs, but maybe it would have been better if I didn’t see them.
“We will do our best to defend the yellow jersey. “
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