USC trailed late in the fourth quarter Saturday night against Notre Dame, needing a touchdown to win at the Coliseum.
Quarterback Mitch Mustain, a patient fifth-year senior making his first start for the Trojans, converted a fourth-down pass as his team drove toward a come-from-behind victory.
But Mustain's final attempt was intercepted at the goal line, giving Notre Dame a 20-16 win that ended the Trojans' near-decade of domination in the intersectional series.
The loss was USC's first in the last nine games against the Fighting Irish and dropped the Trojans to 7-5.
A few weeks ago, USC was considering the possibility of a 10-win season.
Now after losses to Oregon State and the Irish, Coach Lane Kiffin will try to salvage his first season with a victory next week over UCLA.
"That was a tough locker room," Kiffin said on his way out of the stadium. "We had a chance to send off the seniors having never lost to Notre Dame.
"We have another game, so we just have to go back to work."
Notre Dame USC
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