Induced transcription through CAG repeats in human cells increases repeat contraction approximately 15-fold in both confluent and proliferating cells. Repeats are stabilized against contraction by siRNA knockdown of MSH2, MSH3 or XPA, but not by knockdown of MSH6, XPC or FEN1. These results define a pathway for CAG.CTG repeat contraction that is initiated by transcription, depends on elements of mismatch and nucleotide-excision repair and does not require DNA replication.