Purpose: Several lines of evidence suggest that diet and weight gain may be important environmental factors implicated in prostate carcinogenesis, especially in tumor progression. The purpose of this study was to evaluate obesity at different ages in a well-characterized cohort of prostate cancer patients treated with prostatectomy and to develop a prognostic model that incorporates body mass index (BMI) as a measure of obesity. Experimental Design: We carried out a prospective study of 526 patients registered at the M.D. Anderson Cancer Center from 1992 to 2001. Kaplan-Meier and Cox proportional hazard analyses were done. Results: During an average follow-up of 54 months, 97 (18%) post-prostatectomy patients experienced biochemical failure. Patients who were obese (BMI ≥ 30 kg/m 2 ) at diagnosis had a higher rate of biochemical failure than nonobese men ( P = 0.07). Those obese at 40 years had an even greater rate of biochemical failure ( P = 0.001). Higher BMI at diagnosis hazard ratio (HR), 1.07; P = 0.01 and Gleason score = 7(4 + 3) and ≥8 (HR, 3.9; P = 0.03 and HR, 10.0; P ≤ 0.001, respectively) remained significant independent predictors of biochemical failure in multivariate analysis. Men who gained weight at the greatest rate (>1.5 kg/y) between 25 years and diagnosis progressed significantly sooner (mean time, 17 months) than those who exhibited a slower weight gain (mean time, 39 months; P trend = 0.005). The inclusion of obesity to the clinical nomogram improved performance. Conclusions: Our findings validate the importance for a role of obesity in prostate cancer progression and suggest a link to the biological basis of prostate cancer progression that can be therapeutically exploited.