Clinicopathological studies support a broad classification of endometrial carcinoma into two major types, designated as type I and type II, which correlate with their biological behavior. More recently, molecular studies have provided further insights into this classification scheme by elucidating the genetic events involved in the development and progression of endometrial carcinoma. Microsatellite instability and mutations in the PTEN gene have been widely associated with type I (endometrioid) endometrial carcinoma, while p53 mutations have been identified in the majority of type II endometrial carcinoma, of which uterine serous carcinoma is the prototype. Uterine clear cell carcinoma (UCC) is an uncommon variant of endometrial carcinoma, and clinicopathological studies have produced conflicting results regarding its biological behavior with 5-year survival ranging from 21 to 75%. The molecular characteristics of endometrioid and serous carcinoma have been studied extensively; however, there have been few molecular genetic studies of the clear cell subtype. In this study, we evaluated 16 UCCs (11 pure and 5 mixed) for mutations in the p53 gene, PTEN gene and for microsatellite instability. Although we found that these alterations were uncommon in pure clear cell carcinomas, all three were identified. In addition, two cases of mixed serous and clear cell carcinoma showed an identical mutation of the p53 gene in the histologically distinct components and one case of mixed clear cell and endometrioid carcinoma had identical mutations in the PTEN and p53 genes, and microsatellite instability in both components. Our data suggest that UCC represent a heterogeneous group of tumors that arise via different pathogenetic pathways. Additional molecular studies of pure clear cell carcinoma are required to further elucidate the genetic pathways involved in its development and progression.