Despite recent studies, the molecular genetic events responsible for the development of uterine endometrioid carcinoma (UEC) remain incompletely characterized. Mutations in the beta-catenin (CTNNB1) gene have been recently reported in a small percentage of UECs and in the endometrioid variant of ovarian carcinoma suggesting that the Wnt signal transduction pathway is involved in the development of female genital tract tumors with endometrioid morphology. The Wnt pathway is a critical pathway in the development of colorectal cancer (CRC) with mutations occurring in the beta-catenin (CTNNB1) or adenomatous polyposis coli (APC) genes in 10 to 15% and 85% of cases, respectively. Because UEC and CRC share other molecular genetic alterations and histologic features and previous studies of UEC have not reported an analysis of the APC gene, we chose to further elucidate the role of the Wnt pathway in UEC. To this end, we analyzed 32 cases of UEC for mutations of the CTNNB1 and APC genes. Mutations of CTNNB1 were present in six of 32 (18%) cases: four grade 1 carcinomas, one grade 2, and one grade 3 carcinoma. Five missense mutations were identified, three involving Ser/Thr phosphorylation sites and two adjacent to a Ser phosphorylation site. One case contained a deletion encompassing codons 34 to 37, which includes a Ser phosphorylation site. No mutations resulting in truncation of the APC protein were found. Our results support a role for the Wnt signaling pathway via mutation of CTNNB1, but not APC, in the development of a subset of UECs.