Nibali maintained his 31-second lead over nearest chaser Nicolas Roche. Alejandro Valverde and Christopher Horner were tied for third overall at 46 seconds behind, while Joaquim Rodriguez was fifth at 2 minutes, 33 seconds off Nibali's pace.
Nibali, who is aiming to add to his Giro d'Italia win from earlier this summer, appeared to be almost fully recovered from a bee sting that had caused his face to swell.
On Saturday, the riders dispute the first of three stages in the Pyrenees with a 156-kilometer (97-mile) route starting at Baga and finishing in the principality of Andorra. The 14th stage features a special-category climb and ends with a first-category summit finish.
Weather reports forecast the end to the sunny and warm conditions riders have enjoyed so far. A drop in temperature and rain is expected in the mountains.
The three-week grand tour finishes in Madrid on Sept. 15.