The present study was undertaken to define the gene(s) of importance on the long arm of chromosome 18 (chromosome 18q) in endometrial carcinomas. We analyzed loss of heterozygosity (LOH) at 3 loci on chromosome 18q and DCC gene expression by the reverse-transcriptase/polymerase chain reaction (RT-PCR) method. Among 61 tumors that were informative, 16 (26%), estimated to be a minimum number, showed allelic losses at one or more chromosome 18q loci. Deletions in these tumors possibly involved the region within or near the chromosome 18q 21.3 band where the DCC gene was localized. Moreover, the incidence of altered DCC mRNA expression was high in these tumors. Appropriate transcription was lost in 5 of 7 (71%) carcinoma cell lines in addition to 14 of 28 (50%) surgically resected tumors. Histopathological differentiation and clinical stage of disease were not related to LOH frequency or to DCC mRNA expression. These results suggest that the target for allelic loss on chromosome 18q seen in endometrial carcinomas is the DCC gene, and that inactivation of this gene may be critical for the development of most endometrial carcinomas.