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Background Single-nucleotide polymorphisms (SNPs) in five chromosomal regions -- three at 8q24 and one each at 17q12 and 17q24.3 -- have been associated with prostate cancer. Each SNP has only a moderate association, but when SNPs are combined, the association may be stronger. Methods We evaluated 16 SNPs from five chromosomal regions in a Swedish population (2893 subjects with prostate cancer and 1781 control subjects) and assessed the individual and combined association of the SNPs with prostate cancer. Results Multiple SNPs in each of the five regions were associated with prostate cancer in single SNP analysis. When the most significant SNP from each of the five regions was selected and included in a multivariate analysis, each SNP remained significant after adjustment for other SNPs and family history. Together, the five SNPs and family history were estimated to account for 46% of the cases of prostate cancer in the Swedish men we studied. The five SNPs plus family history had a cumulative association with prostate cancer (P for trend, 3.93x10(-28)). In men who had any five or more of these factors associated with prostate cancer, the odds ratio for prostate cancer was 9.46 (P=1.29x10(-8)), as compared with men without any of the factors. The cumulative effect of these variants and family history was independent of serum levels of prostate-specific antigen at diagnosis. Conclusions SNPs in five chromosomal regions plus a family history of prostate cancer have a cumulative and significant association with prostate cancer.