Prostate cancer (CaP) is the most commonly diagnosed non-skin cancer and the second leading cause of cancer death in American men. The etiology of CaP is not fully understood. Because most of the DNA adducts generated by some CaP-related carcinogens, including polycyclic aromatic hydrocarbons, heterocyclic amines, and pesticides, are removed by the nucleotide excision repair (NER) pathway, we pilot tested the hypothesis that CaP is associated with deficient NER capacity (NERC), measured by a plasmid-based host reactivation assay. Using cryopreserved lymphocytes collected in an ongoing, clinic-based case-control study, our results showed that the mean NERC was significantly lower (P = 0.03) in 140 cases (mean +/- SD, 8.06 +/- 5.17) than in 96 controls (9.64 +/- 5.49). There was a significant association between below-median NERC and CaP risk: odds ratio (OR), 2.14; 95% confidence interval (CI), 1.19-3.86, after adjustment for age, race/ethnicity, smoking history, benign prostatic hyperplasia, and family history. This association was stronger in younger (<60 years of age) subjects (OR, 3.98; 95% CI, 1.13-14.02) compared with older (> or = 60) subjects (OR, 1.74; 95% CI, 0.90-3.37). When we stratified NERC values by quartiles of controls, there was a significant dose-dependent association between lower NERC and elevated CaP risk (p (test for linear trend), 0.01). Compared with the highest quartile of NERC as the referent group, the adjusted ORs for the 75th, 50th, and 25th quartiles were: 1.09 (95% CI, 0.46-2.59); 1.81 (95% CI, 0.77-4.27); and 2.63 (95% CI, 1.17-5.95), respectively. This pilot study is the first direct evidence associating deficient NERC with human CaP risk.