Ovarian serous cystadenomas are common ovarian lesions that may be precursors of serous borderline tumors, which can in turn progress to low-grade serous carcinomas. It has been shown that low-grade serous carcinoma and serous borderline tumors are characterized by frequent mutations in BRAF or KRAS genes, but the mutational status of these genes in serous cystadenomas and the clonal nature of serous cystadenomas have not been fully investigated. We isolated cyst-lining epithelium from 30 consecutive serous cystadenomas, and analyzed their BRAF and KRAS mutational status. Wild-type sequences of BRAF and KRAS were detected in all specimens. Using the human androgen receptor gene as a polymorphic marker, we also examined the clonal status of epithelial cells in all of the serous cystadenomas. Four of 29 (14%) informative specimens were monoclonal based on the methylation pattern. These monoclonal cystadenomas were significantly (P<0.01) larger in size (>8 cm) than the nonclonal cystadenomas. These data indicate that serous cystadenomas do not contain mutations in either BRAF or KRAS genes and that most serous cystadenomas are polyclonal. Accordingly, it appears that serous cystadenomas develop as a hyperplastic expansion from epithelial inclusions with a clonal/neoplastic transformation occurring in a subset of them.