Herein, we aimed to examine whether the association of body mass index (BMI) with prostate cancer (PCa) at biopsy differs according to genetic susceptibility.In a multicenter prospective cohort including 1120 men undergoing diagnostic prostate biopsy in China, we evaluated the interaction between BMI and genetic risk score (GRS) comprising 24 PCa-associated single nucleotide polymorphisms (SNPs), as well as a GRS consisting of 7 SNPs derived from an East-Asian population. The genetic risk was defined as low, intermediate, or high when GRS fell in the first, second, and third tertiles, respectively.We observed a significant interaction between BMI and PCa GRS (Pinteraction = 0.047), suggesting that the predictive value of BMI on PCa was strongly modified by genetic susceptibility. In men with high genetic risk, BMI was an independent predictor of PCa (odds ratio [OR] = 1.167, P = 0.008) after adjusting for conventional risk factors. The relationship between BMI and PCa risk diminished (P = 0.990) in men with low genetic risk. The interaction was more pronounced with the East-Asian GRS (Pinteraction = 0.032), suggesting that the overall GRS interaction most likely occurs through genetic susceptibility in the East-Asian population.Our results suggest that the predictive effect of BMI on the PCa risk is strongly modified by individual genetic susceptibility. The association is more positive among men with high genetic risk for PCa.