The tumor suppressor gene adenomatous polyposis coli has been shown to be altered in colon and esophageal cancers. Because of similar causes of oral and esophageal cancers, we investigated allelic deletion of the adenomatous polyposis coli gene in oral cancers by examining tumor cells of persons normally heterozygous at a polymorphic restriction site in adenomatous polyposis coli. Deoxyribonucleic acid was extracted from 20 formalin-fixed microdissected sections and one fresh specimen of oral squamous cell carcinomas and amplified with the use of the polymerase chain reaction. The amplified deoxyribonucleic acid was digested with Rsa I, subjected to polyacrylamide gel electrophoresis, and examined for loss of heterozygosity in adenomatous polyposis coli alleles. Samples from nine persons were homozygous for the adenomatous polyposis coli restriction site in both tumor and normal tissues and thus were uninformative. Three of the 12 samples from heterozygous persons showed loss of one adenomatous polyposis coli allele in tumor tissues. The loss of an adenomatous polyposis coli gene allele in 25% of the carcinomas examined suggests that inactivation of adenomatous polyposis coli or another neighboring gene on chromosome 5q may be involved in carcinogenesis in the oral cavity.