Background: Increasing BMI is associated with an increased risk of mortality; however, quantifying weight gain in men undergoing ADT for prostate cancer (PC) as stratified by baseline BMI remains unexplored and was the subject of the current study. Methods: Between 1995 and 2001, 206 men with unfavorable-risk prostate cancer were enrolled on a randomized trial evaluating the impact on survival of adding 6-months of ADT to radiotherapy (RT). BMI, both at baseline and after therapy, was available in 171 men who formed the study cohort. The primary endpoint was weight gain of ≥10 lbs by the 6-month follow-up. Logistic regression multivariable analysis was performed to assess whether baseline BMI or treatment-received was associated with this endpoint adjusting for comorbidity and known PC prognostic factors. Results: By the 6 month follow-up, 12 men were observed to have gained ≥10 lbs of which 10 (83%) were treated with RT and ADT and, of these, 7 (70%) were obese at randomization. As shown in the table, men treated with RT as compared to RT and ADT were significantly less likely to experience a weight gain of ≥ 10 pounds (adjusted odds ratio (AOR): 0.18 [95% confidence interval (CI) 0.04 - 0.89]; p = 0.04); whereas this risk was significantly increased with increasing BMI (AOR: 1.15 [ 95% CI 1.01 – 1.31]; p = 0.04). Moreover, weight gain persisted at 2 years for the obese men who gained ≥ 10 lbs after treatment with RT and ADT (median: 13.0 lbs; range: 9.0 to 21.0). Conclusions: Consideration should be given to avoiding ADT use in obese men with low or favorable-intermediate risk PC where improved cancer control has not been observed, but a shortened life expectancy from weight gain is expected. Clinical trial information: NCT00116220.