Objectives: To examine whether the predictive performance of prostate-specific antigen (PSA) and PSA-related markers for prostate cancer (PCa) is modified by body mass index (BMI).Patients and Methods: Patients with a PSA 2-10ng/mLwho underwent multicore prostate biopsies were recruited from three tertiary centers.Serum markers measured included total PSA (tPSA), free-to-total PSA (f/tPSA), p2PSA,percentage of p2PSA (%p2PSA), and prostate health index (PHI).The association between serum markers and PCa risk was assessed by logistic regression.Predictive performance for each marker was quantified using the area under the receiver operator curves (AUC).Results: Among 516 men, 18.2% had PCa at biopsy.For all tested markers, theirpredictive valueon PCa risk was lower in overweight patients compared to normal weight patients.We found statistically significant interactionsbetween BMI and tPSA (P=0.0026) and p2PSA (P=0.038).PHI achieved an AUC of 0.872 in normal weight patients and 0.745 in overweight patients, which outperformed the other predictors regardless of BMI category.The specificity of PHI at 90% sensitivity was lower in overweight men compared to normal weight men (20.5% vs.60.9%).Conclusions: The predictive performance of tPSA and p2PSA for PCa risk was significantly modified by BMI.Although PHI achieved better discriminative ability than conventional markers in overweight men, it still lacks specificity for identifying PCa at biopsy.Impact: These findings highlight BMI should be consider as an adjusting factor when assessing the diagnostic performance of PSA-related markers.