194 Background: Men with diabetes mellitus (DM) are less likely to be diagnosed with prostate cancer (PC). As diabetic men have lower PSA values, it is unclear if this is due to reduced PC incidence or lower biopsy rates from the lower PSA. To account for differential biopsy rates, we explored the link between DM and risk of PC and high-grade PC in the REDUCE trial. We also explored if these associations differed by body mass index (BMI) as a prior study suggested BMI may modify the effect of DM on PC aggressiveness. Methods: The 4-year REDUCE study tested the effect of dutasteride 0.5 mg daily on PC risk reduction in men with PSA of 2.5-10.0 ng/mL and a negative prostate biopsy. Men underwent study-mandated biopsies at 2 and 4 years regardless of PSA. DM was determined by self report at baseline. BMI (kg/m²) was calculated from height and weight measured at baseline. The risk of PC and high-grade PC (Gleason 7-10) was determined using multivariate logistic regression adjusting for age, race, BMI, PSA, and treatment arm. Effect modification by BMI (<25, 25-29.9, and >30 kg/m²) was tested via interactions. Results: Of 8,122 men in the REDUCE trial, 499 (6.1%) had DM. Diabetic men were older (63.8 vs. 62.7 yrs, p=0.001) with a higher BMI (median BMI 27.8 vs. 26.8, p<0.0001). After adjusting for age and BMI, diabetic men had lower PSA values (p=0.04). On multivariate analysis, DM was not associated with PC risk (OR 0.96, 95% CI 0.75-1.22, p=0.74). When stratified by BMI, DM was not associated with PC risk in any group (all p>0.23) and the results did not vary by BMI category (p-interaction=0.13). DM was not associated with high-grade PC on multivariate analysis (OR 0.88, 95% CI 0.58-1.33, p=0.55). When stratified by BMI, though DM was not associated with high-grade PC risk in any single group (all p>0.14), there was a suggestion of effect modification by BMI (p-interaction=0.056) with a positive association between DM and high-grade PC in obese men (OR 1.32) and an inverse association in normal weight men (OR 0.35). Conclusions: In the REDUCE trial, when all men undergo biopsy regardless of PSA, DM is not associated with lower PC risk, but rather equal PC risk and equal risk of high-grade PC. These results suggest the lower rate of PC among diabetic men in prior studies may be driven by lower biopsy rates from lower PSA. [Table: see text]