BACKGROUND: PSA is central to referrals for prostate biopsy but has low specificity for aggressive prostate cancer. This study evaluates the 4Kscore (OPKO Diagnostics) versus total PSA in predicting short- and long-term risks of aggressive prostate cancer. METHODS: Baseline blood samples from 1,658 men diagnosed with prostate cancer (median diagnosis time = 8.6 years) and 1,658 matched controls in the European Prospective Investigation into Cancer and Nutrition were analyzed. Discrimination for the 4Kscore and total PSA was assessed using the AUC with 95% confidence intervals (CI) via bootstrapping. RESULTS: For high-grade tumors, AUCs were 0.69 (95% CI, 0.66-0.72) for the 4Kscore and 0.75 (95% CI, 0.73-0.78) for total PSA. For advanced-stage disease, AUCs were 0.71 (95% CI, 0.66-0.75) for the 4Kscore and 0.77 (95% CI, 0.73-0.80) for total PSA. Similar findings were observed for other aggressive cancer endpoints. Among men with PSA >2 ng/mL, the 4Kscore had better discrimination than PSA for overall prostate cancer, high-grade disease, and prostate cancer death but only in men <60 years at recruitment. CONCLUSIONS: In this large European study, the 4Kscore did not significantly improve the prediction of clinically significant prostate cancer compared with total PSA, except in younger men with elevated PSA. IMPACT: The findings underscore the limited utility of the 4Kscore in improving medium- to longer-term risk prediction over PSA, with potential benefits restricted to younger men with elevated PSA.