Familial cancer clusters provide a unique opportunity to elucidate the molecular mechanisms central to the development of malignancy. We have identified four families in which 11 members developed epithelial ovarian cancer. The clinical course of disease in these individuals with familial ovarian cancer appears to be very different from that of patients with nonfamilial ovarian cancer. In order to compare these disease states, 34 cases matched for age at diagnosis (57 years), tumor histology (all adenocarcinomas), and a preponderance of advanced grade and FIGO stage of disease were selected. Patients with familial ovarian cancer exhibited a 67% 5-year survival in comparison with a 17% 5-year survival in the nonfamilial ovarian cancer cases. Preliminary studies indicate a lack of overexpression of the HER-2/neu oncogene in the familial cancer members' tumors. This may correlate with the indolent character of their disease. Abnormal p53 tumor suppressor gene expression was noted in four of six cancers tested. We also found germ line p53 mutations in three of the four families, but neither the germ line or tumor p53 prevalence was 100%. This is the first report of germ line p53 mutations associated with familial ovarian cancer and indicates that this gene may play a role in the development of some familial ovarian cancers.