Alterations in microsatellite sequences characterize hereditary nonpolyposis colorectal cancer. This microsatellite instability is due in some kindreds to a germline mutation of the mismatch repair gene hMSH2 on chromosome 2p. Although microsatellite alterations have been reported in other hereditary nonpolyposis colorectal cancer-associated tumors including endometrial and gastric cancers, such changes were not detected in most other major neoplasms. We found that 15 of 33 (45%) primary small cell lung cancers, tumors not found in the hereditary nonpolyposis colorectal cancer syndrome, displayed alterations of microsatellite loci which consisted of deletions or expansions of (CA)n dinucleotide repeats. In 8 of these 15 neoplasms, microsatellite instability was detected in more than 10% of all tested alleles. However, small cell lung cancers that revealed instability contained widespread allelic loss and had a uniformly poor prognosis. These results expand considerably the known spectrum of tumors with microsatellite instability.