Clermont had not been beaten since October, but they were brought back down to earth by Top 14 champions Castres.
Castres halted leaders Clermont Auvergne's 13-match unbeaten with a 24-16 victory, while high-flying La Rochelle and Lyon claimed Top 14 wins on Saturday.
Clermont had not suffered a defeat since October, but they came unstuck against the champions at Stade Pierre-Fabre.
Castres duo Armand Batlle and Martin Laveau scored first-half tries before Peceli Yato's five-pointer reduced the deficit to 15-8 at the interval.
Remy Grosso crossed early in the second half to make it a two-point game, but Benjamin Urdapilleta took his tally from the tee to 11 points and Rory Kockott was on target with a penalty to give Castres breathing space after Greig Laidlaw split the posts at the other end.
Defeat for Franck Azema's men was just their third of the season and Toulouse can replace them at the summit with a win over lowly Grenoble on Sunday.