Susceptibility to pancreatic adenocarcinoma appears to be linked to germ-line mutations in genes causing various familial cancer syndromes. The objectives of this study were to estimate the proportion of unselected pancreatic cancer patients belonging to hereditary cancer syndrome families and to determine the frequency ofp16, BRCA1, BRCA2, hMSH2, and hMLH1 germ-line mutations in patients with a personal or family history of cancer. The study population consisted of 102 patients with histologically verified pancreatic adenocarcinoma, unselected for age, sex, family history, or ethnic origin. Patients completed a family history questionnaire and provided blood for mutation analysis. Three-generation pedigrees were constructed and classified as high risk/familial, intermediate risk/ familial, intermediate risk/nonfamilial, or low risk according to defined criteria. High- and intermediate-risk cases were analyzed for germ-line mutations using a combination of methods. Thirty-eight of 102 (37%) patients were characterized as high or intermediate risk, and the remainder were classified as low risk. Germ-line mutations were identified in five (13%) of these cases [one in p16 (I49S); one in BRCA1 (5382 insC); and three in BRCA2 (6174delT)]. The BRCA1 and BRCA2 mutations were identified in Ashkenazi Jewish patients. Four of the mutation carriers had strong family histories of the syndromes associated with the mutated genes. No mutations were identified in patients in whom the sole risk factor was a family history of pancreatic cancer, and only one mutation was found among patients with early-onset disease. We conclude that known causes of genetic predisposition are an important risk factor in a small proportion of pancreatic cancer patients, especially if associated with a strong family history of syndromes associated with the disease. The lack of detectable germ-line mutations in most high- and intermediate-risk cases suggests that there are probably additional, as yet unidentified genes predisposing to this disease.