Abstract Circadian genes are responsible for maintaining the ancient adaptation of a 24-hour circadian rhythm and influence a variety of cancer-related biological pathways, including the regulation of sex hormone levels. However, few studies have been undertaken to investigate the role of circadian genes in the development of prostate cancer, the most common cancer type among men (excluding nonmelanoma skin cancer). The current genetic association study tested the circadian gene hypothesis in relation to prostate cancer by genotyping a total of 41 tagging and amino acid–altering single nucleotide polymorphisms (SNP) in 10 circadian-related genes in a population-based case-control study of Caucasian men (n = 1,308 cases and 1,266 controls). Our results showed that at least one SNP in nine core circadian genes (rs885747 and rs2289591 in PER1; rs7602358 in PER2; rs1012477 in PER3; rs1534891 in CSNK1E; rs12315175 in CRY1; rs2292912 in CRY2; rs7950226 in ARNTL; rs11133373 in CLOCK; and rs1369481, rs895521, and rs17024926 in NPAS2) was significantly associated with susceptibility to prostate cancer (either overall risk or risk of aggressive disease), and the risk estimate for four SNPs in three genes (rs885747 and rs2289591 in PER1, rs1012477 in PER3, and rs11133373 in CLOCK) varied by disease aggressiveness. Further analyses of haplotypes were consistent with these genotyping results. Findings from this candidate gene association study support the hypothesis of a link between genetic variants in circadian genes and prostate cancer risk, warranting further confirmation and mechanistic investigation of circadian biomarkers in prostate tumorigenesis. [Cancer Res 2009;69(24):9315–22]