Rett syndrome is usually sporadic, but rare pedigrees with nonpenetrance in obligate carriers and possible anticipation suggest that it could be caused by a triplet repeat expansion (TRE). Rett probands and controls were systematically screened for expansions of any of the 10 possible triplet repeats by using a modified Repeat Expansion Detection (RED) assay that had been shown to detect expanded disease alleles in myotonic dystrophy and Huntington disease. No significant expansions were found in 26 sporadic and six familial Rett probands. Our results exclude the possibility that Rett syndrome is caused by a large TRE. We cannot exclude, however, causation by a small TRE that is masked by the background of longer polymorphic repeats in the normal population.