Abstract Given that androgens exert their effects on target tissues through androgen receptor (AR) binding, polymorphic variation in the AR gene may influence prostate cancer development. Studies examining the AR CAG and GGC repeat polymorphisms in relation to prostate cancer risk, however, have yielded conflicting results. In a case-control study of prostate cancer nested in the β-carotene and Retinol Efficacy Trial, we previously found suggestive evidence of reduced risk in men with a small number of AR CAG [<22 versus ≥22: odds ratio (OR), 0.89; 95% confidence interval (CI): 0.65-1.23] or GGC [≤17 versus >17: OR, 0.80; 95% CI: 0.57-1.12] repeats. The possibility that these associations are more pronounced in certain subgroups of men, with respect to level of circulating sex steroid hormones, has not yet been examined. In the same population of 300 cases and 300 controls, we now explore whether prostate cancer risk associated with CAG or GGC repeat length may differ by levels of serum testosterone, estradiol, androstenedione, dehydroepiandrosterone sulfate, 3α-androstanediol glucuronide, and sex hormone binding globulin concentrations. To cases diagnosed from 1987-1998 who had blood drawn from 0.5 to 8.5 (mean: 3) years prior, controls who were free of prostate and lung cancer were matched on the basis of age, race, study center, time of blood draw, time from enrollment to blood draw, and year of randomization. We found no trend in prostate cancer risk associated with short (≤17) GGC repeat length across thirds of the distribution of the hormones, except for estradiol. For men in the lowest, middle, and highest third of total estradiol, the ORs (95% CIs) were 1.16 (0.65-2.10), 0.87 (0.50-1.72), and 0.50 (0.27-0.92), respectively (p-interaction=0.14). A similar, but weaker association pattern was noted across thirds of free estradiol. No clear differences in the relation of CAG repeat length and prostate cancer risk across levels of each hormone were found. Since the observed positive results may be due to chance, further investigation is needed to determine whether AR GGC repeat length and circulating sex steroid hormone levels interact to alter prostate cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2858.