Epithelial ovarian cancer comprises three major histological subtypes (serous, mucinous, and endometrioid), and it is becoming clear that the developmental pathways for these subtypes are fundamentally different. In particular, endometrioid ovarian cancers probably arise by the malignant transformation of ectopic endometrial implants called endometriosis and not the ovarian surface epithelium. The PTEN/MMAC gene on chromosome 10q23 is a tumor suppressor implicated in the pathogenesis of a wide variety of malignancies, but to date, somatic mutations in PTEN have not been identified in studies of predominantly serous ovarian cancers. In endometrial cancers, PTEN mutations are very common in tumors of the endometrioid type but have rarely been found in serous types, and we hypothesized that a similar histological subtype bias might be occurring in ovarian cancer. We have analyzed 81 ovarian tumors, including 34 endometrioid, 29 serous, 10 mucinous, and 8 clear cell tumors, for loss of heterozygosity (LOH) on 10q23 and for mutations in all 9 coding exons of PTEN. LOH was common among the endometrioid (43%) and serous (28%) tumors but was infrequent among the other histological subtypes. Somatic PTEN mutations were detected in seven (21%) of the endometrioid tumors, and in all informative cases, the mutation was accompanied by loss of the wild-type allele. One mucinous tumor without 10q23 LOH was shown to harbor two somatic PTEN mutations. In this tumor, the histological appearance of the mucinous areas was atypical, and the mucinous areas contained foci of endometrioid differentiation. The majority of tumors with PTEN mutations were grade 1 and/or stage 1, suggesting that inactivation of PTEN is an early event in ovarian tumorigenesis. No PTEN mutations were found among the serous or clear cell tumors. The identification of frequent somatic PTEN mutations in endometrioid ovarian tumors indicates that it plays a significant role in the etiology of this subtype. The absence of mutations in other histological subtypes is consistent with the hypothesis that epithelial ovarian cancers arise through distinct developmental pathways.