Background: The ELAC2 gene has been proposed to be a prostate cancer susceptibility gene and is being referred to as HPC2, in part because three case-control studies suggested that two common polymorphisms (Ser217Leu and Ala541Thr) are associated with risk. However, four subsequent larger studies have not confirmed this association. In five of the seven total studies, subject selection was influenced by prostate-specific antigen (PSA) levels. We examined the association and possible effect of subject selection in a larger study and a meta-analysis. Methods: In a population-based study in Australia, 825 case patients and 732 control subjects were genotyped for the Ser217Leu and Ala541Thr polymorphisms of ELAC2. Odds ratios (ORs) for prostate cancer were estimated by unconditional logistic and polytomous regression. A meta-analysis was conducted combining our data with those from seven published studies. The association of genotype with the logarithm of plasma PSA levels in control subjects was analyzed by linear regression. Results: The ORs for prostate cancer were 0.74 (95% confidence interval [CI] = 0.50 to 1.09) for Leu217 homozygotes and 1.01 (95% CI = 0.68 to 1.50) for Thr541 heterozygotes and homozygotes compared with Ser217 and Ala541 homozygotes, respectively. ORs were not changed by excluding control subjects with elevated PSA levels. Among control subjects, there were no statistically significant associations between genotype frequencies and PSA level for either polymorphism (both P>.4 . The meta-analysis gave pooled OR estimates of 1.04 (95% CI = 0.85 to 1.26) for Leu217 homozygotes and 1.18 (OR = 0.98 to 1.42) for Thr541 homozygotes and heterozygotes. Conclusion: There is no evidence that either ELAC2 polymorphism is associated with prostate cancer or PSA level.