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Objective: To clarify the origin of defective mismatch repair (MMR) in sporadic endometrial cancers with microsatellite instability (MSI), a thorough mutation analysis was performed on the human mismatch repair gene MSH3. Methods: Twenty-eight MSI-positive endometrial cancers were investigated for mutations in the human mismatch repair gene MSH-3using single-strand conformation variant (SSCV) analysis of all 24 exons. All variants were sequenced. Loss of heterozygosity was investigated at all MSH3polymorphisms discovered. A subset of tumors were investigated for methylation of the 5' promoter region of MSH3using Southern blot hybridization. Results: An identical single-base deletion (?A) predicted to result in a truncated protein was discovered in six tumors (21.4%). This deletion occurs in a string of eight consecutive adenosine residues (A8). Because simple repeat sequences are unstable in cells with defective MMR, the observed mutation may be an effect, rather than a cause, of MSI. Evidence of inactivation of the second MSH3allele in tumors with the ?A mutation would strongly support a causal role for these MSH3mutations. However, there was no evidence of a second mutation, loss of sequences, or methylation of the promoter region in any of the tumors with the ?A mutation. Conclusion: Although the ?A mutation is a frequent event in sporadic MSI-positive endometrial cancers, it may not be causally associated with defective DNA MMR.