Abstract Epidemiologic and experimental data suggest that soy may prevent prostate cancer and be beneficial for men with prostate cancer. The mechanisms by which soy may be protective are unclear. Effects of soy constituents on steroid hormones and on angiogenesis, apoptosis, and the insulin growth factor [IGF] axis may be involved. This was examined in a randomized controlled clinical trial testing whether soy reduces biochemical recurrence after radical prostatectomy. Men at high risk for PSA failure after surgery were randomized to a daily soy protein supplement or a casein-based placebo (20 g protein/day) as beverage powders (Solae). The soy and placeboi supplements were identical in composition, except for the protein source. The soy supplement provided 24-26 mg genistein and 40-43 mg total isoflavones daily. The placebo did not contain these or other soy-specific constituents. Self-reported compliance was excellent, serum isoflavones are measured as independent compliance measure, and only few minimal averse effects occurred. Serum samples were taken at baseline, and after 2, 4, 8, 12, and 18 months on intervention. Using ELISA and enzyme immuno-assays, we measured serum indicators of angiogenesis (VEGF and bFGF), global apoptotic activity (soluble Fas [sFas] and Fas ligand [FasL]) and the IGF axis (IGF-1 and IGF binding protein 3 [IGFBP3]) in 8-12 subjects/treatment group, and serum testosterone [T], 17β-estradiol [E2], sex hormone binding globulin [SHBG], and PSA in 12 subjects/group. Generalized Estimating Equations were used to analyze the longitudinal data. FasL increased slightly over time in the placebo group (p=0.05), but sFas did not and there were no differences in change over time between the groups for either. IGF-1 increased slightly over time in placebos (p=0.06), but IGFBP3 did not and there were no differences in change over time between the groups for these endpoints. In contrast, while T levels did not change over time in the placebo group, T levels decreased significantly (p=0.03) from baseline over time by approx. 15% in the soy group. There were no diffrence over time in E2 and SHBG levels in either group. While literature data indicate a lack of soy effects on T and SHBG, this is the first report of soy effects on circulating T and SHBG with repeated serum sampling for up to 1.5 years. This is also the first report of soy effects on serum VEGF, bFGF, sFas, and FasL. The absence of effects on the IGF axis is in line with other studies. Thus, daily consumption of 20 g of soy protein isolate for 18 months slightly reduced serum T levels over time, but did not affect E2, SHBG, and indicators of angiogenesis, apoptosis, and the IGF axis. Despite small sample sizes, several of the group comparisons were close to statistical significance, providing some direction for further studies. (Supported by CA27790 & CA166195 from NIH and the Prevent Cancer Foundation) 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 2892.