Over the last decade, epidemiologic evidence has accumulated in favor of a significant but heterogeneous hereditary component in prostate cancer (PC) susceptibility. In order to map and clone PC susceptibility genes, stratification of PC families into genetically homogeneous groups appears to be a key issue. Subset definition based on age at diagnosis, presumed mode of inheritance, number of affecteds per family and coaggregation of PC with other cancers has already proven successful in some studies. Previously, the finding of the coaggregation of malignancies of the central nervous system within PC families helped to link a prostate-brain cancer susceptibility gene (CAPB) to chromosome 1p36. In this study, we evaluate the risk of PC and malignancies at other sites among first-degree relatives of a large population-based group of Dutch PC patients. A population-based family case-control study was initiated that included Caucasian PC patients newly diagnosed between July 1996 and December 1999. Information on 12,575 first-degree relatives of 704 PC patients and 1,371 controls was collected through postal questionnaires and telephone interviews. All reported PC in first-degree relatives was verified through medical records. In our population, PC has a strong familial component that is reflected by a 2.9-fold increased risk (95% CI = 2.2-3.9) of PC for first-degree relatives of PC patients. This familial risk was somewhat higher among brothers (hazard ratio = 3.9; 95% CI = 2.4-6.4) compared to fathers (hazard ratio = 2.5; 95% CI = 1.7-3.6). Cancers at other sites did not coaggregate with PC. Our data suggest that familial PC, at least in this Western European population, is site-specific, not part of an inherited cancer syndrome.