Hereditary prostate cancer is a complex disease, and in some families it seems to segregate with other cancers. Epidemiological and genetic studies have reported familial clustering of prostate and breast cancers. As part of a genome-wide search for prostate cancer genes, we performed linkage analyses in 27 families with three or more affected men with prostate cancer who had at least one first-degree relative with breast cancer. To maximize homogeneity, we stratified these families by the pattern of breast cancer (one case, n=14; two cases, n=6; any ovarian cancer, n=7). Families were stratified into early- (66 yr) or later-onset (= 66 yr) prostate cancer on the basis of median age at diagnosis. GENEHUNTER was used to compute multipoint NPL scores for prostate cancer linkage using 380 genomic scan markers. Stratified analyses revealed three chromosomal regions with NPL scores of 3.0: (1) chromosome 7q, NPL=3.98 (P=0.002) at markers D7S1826–D7S1805 in later-onset prostate cancer families with breast and ovarian cancer; (2) chromosome 14q, NPL=3.47 (P=0.01) at marker D14S587 in early-onset prostate cancer families with more than two first-degree relatives with breast cancer and (3) chromosome Xq, NPL=3.12 (P=0.003) at marker GATA172D05 in later-onset prostate cancer families with only one relative with breast cancer. None of these families had evidence of significance linkage on chromosomes 13 or 17. These data supply further evidence for prostate cancer susceptibility genes on chromosomes 14 and X, and they highlight a new region of interest on chromosome 7 that may be involved in the etiology of both prostate cancer and breast cancer.