4617 Background: The escalating rate of obesity in the Western world presents a diagnostic challenge when screening for prostate cancer. Increased body-mass index (BMI) disrupts the ability to effectively screen this population due to an associated decrease in serum prostate-specific antigen (PSA) levels and an increase in prostate volume. We therefore sought to understand how BMI impacts the probability of harboring prostate cancer. Methods: Data were collected on 647 referred men with a serum PSA of ≤ 10 ng/ml who underwent an ultrasound-guided prostate biopsy. Variables analyzed included: age, BMI, digital rectal exam (DRE), PSA, PSAD (i.e. PSA ÷ prostate volume), prostate volume, hypoechoic lesions on ultrasound and cancer on biopsy. A one-way ANOVA was performed to determine differences in log2 (PSAD) among BMI groups (<25 kg/m2 vs. 25–30 kg/m2 vs. >30 kg/m2). Multivariate logistic regression analysis was performed to estimate the odds-ratio (OR) and 95% confidence intervals (CI). Results: Prostate cancer was detected in 19.2 % of patients. ANOVA showed the mean PSAD to be significantly different in the three BMI groups (F value = 7.1, p = .0009). The mean PSAD significantly decreased as the BMI level increased (p = .0002). Independent pre-biopsy predictors of prostate cancer were tabulated (see below). Conclusions: Obesity was associated with a decrease in PSA density. The multivariate logistic regression revealed that the effect of PSAD on cancer detection was significantly modified by BMI. Specifically, the OR associated with a doubling of PSAD was 1.7 when BMI was <25 kg/m2 vs. 2.1 when BMI was ≥25 kg/m2). This interaction was an independent predictor of prostate cancer risk, along with DRE and ultrasound findings. These data underscore the need to consider BMI as a potential effect modifier of traditional clinical risk factors for prostate cancer. The dramatic rise in obesity in the United States makes this effect modification particularly relevant. [Table: see text] No significant financial relationships to disclose.