Use of tamoxifen for treatment and prevention of breast cancer is becoming increasingly common. Tamoxifen has been associated with increased risk of endometrial carcinoma, although the exact mechanism of action is unknown. The aim of our study was to seek a possible correlation between endometrial carcinoma, tamoxifen exposure and MSI, PTEN, beta-catenin and K-ras abnormalities. A group of 18 patients with endometrial carcinoma following treatment with tamoxifen were selected. A control group included 15 patients with endometrial carcinoma and associated ovarian hyperthecosis and one patient with endometrial carcinoma and adult granulosa cell tumor of the ovary, chosen because both conditions are associated with increased production of estrogen and increased risk of endometrial carcinoma development. The second control group included 27 randomly selected consecutive patients with endometrial carcinoma without identifiable associated conditions. Immunostaining for beta-catenin was performed on all cases; DNA was extracted and amplified by PCR with primers for beta-catenin, K-ras and PTEN genes. BAT-25 and BAT-26 were analyzed to assess for MSI. There were 16 endometrioid endometrial carcinomas, one mixed carcinoma and one clear cell carcinoma among patients in the tamoxifen group. All patients with ovarian hyperthecosis and adult granulosa cell tumor had endometrioid endometrial carcinoma. In the random control group, there were 26 endometrioid endometrial carcinomas and one carcinosarcoma. Immunohistochemical and mutational analysis for beta-catenin showed abnormalities in 4/11 (36%) and 3/10 (30%) informative cases in the tamoxifen group; 7/16 (44%) and 4/15 (27%) informative cases, respectively in the ovarian hyperthecosis group and 1/27 random control cases (4%) (P<0.05). Patients with tamoxifen exposure had more K-ras mutations and fewer PTEN mutations and MSI as opposed to controls, but the results were not statistically significant. In conclusion, there was a direct relationship between tamoxifen exposure and overexpression of beta-catenin oncoprotein, which is known to play a major role in the pathogenesis of estrogen-driven, type I endometrial adenocarcinoma.