Lycopene has been associated with reduced prostate cancer risk, although the results of epidemiological studies have varied. We hypothesize that an effect of lycopene may be modified by XRCC1 genotype and other antioxidants. We used a food-frequency questionnaire to assess lycopene intake in a case-control study of prostate cancer in North Carolina. Plasma alpha-tocopherol and beta-carotene levels were measured using high-performance liquid chromatography. XRCC1 genotypes were detected using polymerase chain reaction-restriction fragment length polymorphism. The final dataset included 77 cases and 174 controls with complete questionnaires, genotyping, and plasma analyses. Among men with the Arg/Arg genotype at codon 399, odds ratios (ORs) for prostate cancer risk associated with medium (732-1,529 microg/day) and high (>1,529 microg/day) lycopene intake were 0.59 (95% confidence interval = 0.23-1.50) and 0.21 (0.06-0.71), respectively (P(trend) < 0.01). Similar analyses for persons with Arg/Gln or Gln/Gln genotypes produced null results. Above-median (1,048 microg/day) lycopene intake combined with above-median levels of alpha-tocopherol and beta-carotene was associated with an OR of 0.11 (0.02-0.65) among men with the Arg/Arg genotype but not those with at least one Gln allele (P(interaction) = 0.01). Although limited by small sample size, these findings indicate that the association between lycopene and prostate cancer is complex and may be modified by other antioxidants and by XRCC1 genotype.