Introduction: In female embryos, the reproductive organs arise from the Mullerian ducts and associated epithelium; these structures regress under the influence of MIS produced by male embryos. The MIS type II receptor (MISIIR) can mediate MIS-induced growth inhibition of malignant ovarian and cervical cells. We propose that endometrial cancers will express the MISIIR and MIS will inhibit endometrial cancer growth. Methods: Human samples were obtained under IRB approval (2002-P-001324). Rat tissue was collected under institutional protocol 1999-N-00138-Rats. Cells lines were purchased from American Tissue and Cell Culture. Tissue and cell samples were analyzed by Western, PCR, growth inhibition assays, and FACS. Results: Western detected MISIIR protein in adult rat uterus; reverse transcriptase PCR detected MISIIR RNA in normal and malignant human endometrium. AN3CA and KLE, two human endometrial cancer cell lines, expressed MISIIR. MIS inhibited AN3CA and KLE cell growth 67.3% (p < 0.0001, n = 4) and 52.5% (p = 0.0041, n = 3), respectively. MIS-treated AN3CA cells demonstrated G1 arrest, increased Caspase 3 cleavage indicating apoptosis, increased levels of cell cycle proteins p107 and p130 and transcription factor E2F3, and decreased levels of transcription factor E2F1. Conclusions: MISIIR is expressed in normal endometrium and in human endometrial cancer. MIS inhibits the growth of two human endometrial cancer cell lines, induces cell cycle arrest and apoptosis in AN3CA cells, and affects proteins important to the control of cell cycle progression. In the future, treatment targets for MIS may broaden to include advanced endometrial cancer