To determine the potential role of PTEN in the process of endometrial carcinogenesis, we examined a series of endometrial carcinoma and hyperplasia of the uterine corpus for the presence of a PTEN mutation. The entire coding region of the gene was screened for the presence of mutations by single-strand conformation polymorphism analysis, and mutations were confirmed by sequencing. We detected mutations in 14 of 57 endometrial carcinomas (13 of 50 endometrioid adenocarcinomas and 1 of 7 nonendometrioid adenocarcinomas) and 7 of 73 endometrial hyperplasias (1 of 24 simple hyperplasias without atypia, none of 16 complex hyperplasias without atypia, and 6 of 33 complex hyperplasias with atypia). Most (88%) mutations were clustered in exons 5, 7, and 8. Of the 24 mutations detected in 21 cases, 12 were frameshifts, 9 were nonsense, 2 were missense, and 1 was a silent mutation. Patients with a PTEN mutation had a better prognosis than those with no PTEN mutation. The presence of PTEN mutations in hyperplasia suggests that PTEN inactivation may occur as an initiating event in endometrial carcinogenesis and is involved in the development of cytologic atypia in hyperplasia.