Homologous recombination was shown to enable the expansion of CTG·CAG repeat sequences. Other prior investigations revealed the involvement of replication and DNA repair in these genetic instabilities. Here we used a genetic assay to measure the frequency of homologous intermolecular recombination between two CTG·CAG tracts. When compared with non-repeating sequences of similar lengths, long (CTG·CAG)n repeats apparently recombine with an ∼60-fold higher frequency. Sequence polymorphisms that interrupt the homogeneity of the CTG·CAG repeat tracts reduce the apparent recombination frequency as compared with the pure uninterrupted repeats. The orientation of the repeats relative to the origin of replication strongly influenced the apparent frequency of recombination. This suggests the involvement of DNA replication in the recombination process of triplet repeats. We propose that DNA polymerases stall within the CTG·CAG repeat tracts causing nicks or double-strand breaks that stimulate homologous recombination. The recombination process is RecA-dependent.