Testing for serum prostate-specific antigen (PSA) levels has been widely used to screen for prostate cancer. However, PSA testing has low specificity and sensitivity because PSA is not prostate cancer-specific. PSA is encoded by the APS gene, and the expression of this gene is regulated by androgens. W. Xue et al. Cancer Res., 60: 839-841, 2000 reported recently that serum PSA levels are associated with a G/A polymorphism at androgen responsive element 1 (ARE1) of APS and/or the CAG repeats in exon 1 of the androgen receptor (AR) gene. This result, if confirmed, may significantly increase the specificity and sensitivity of PSA testing by incorporating genotype-specific thresholds. In this study, we tested for the association between serum PSA levels and these single nucleotide polymorphisms (SNPs) in a large sample of 518 men. For the AR gene, we observed slightly (but not statistically significant) higher mean serum PSA levels in men with shorter CAG repeats (<or=21) or shorter GGC repeats (<or=16). For the ARE1 of the APS, we found slightly (but not statistically significant) lower PSA levels in men with the AA genotype. It is worth noting that this observation is opposite to the findings of W. Xue et al. Cancer Res., 60: 839-841, 2000. We hypothesize that the effects of ARE1 and AR genotypes on mean PSA levels may reflect the effect of other causal polymorphisms in these genes, which are in linkage disequilibrium with these polymorphisms. A systematic approach is required to identify sequence variants in these genes and other related genes, and to test for an association between these variants and PSA levels in large samples.