Alterations in p53 and Rb pathways are observed frequently in epithelial ovarian cancer (EOC).However, their roles in EOC initiation remain uncertain. Using a single intrabursal administration of recombinant adenovirus expressing Cre, we demonstrate that concurrent inactivation of p53 and Rb1 is sufficient for reproducible induction of ovarian epithelial carcinogenesis in mice homozygous for conditional gene alleles. Similarly to progression of disease in women, ovarian neoplasms spread i.p., forming ascites, and metastasize to the contralateral ovary, the lung, and the liver. These results establish critical interactions between p53 and Rb1 pathways in EOC pathogenesis, and provide a genetically defined immunocompetent mouse model of sporadic EOC.