Abstract Background: Studies in men of European ancestry suggest prostate-specific antigen (PSA) as a marker of early prostate cancer development that may help to risk-stratify men earlier in life. Methods: We examined PSA levels in men measured up to 10+ years before a prostate cancer diagnosis in association with prostate cancer risk in 2,245 cases and 2,203 controls of African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. We also compared the discriminative ability of PSA to polygenic risk score (PRS) for prostate cancer. Results: Excluding cases diagnosed within 2 and 10 years of blood draw, men with PSA above the median had a prostate cancer OR (95% CIs) of 9.12 (7.66–10.92) and 3.52 (2.50–5.03), respectively, compared with men with PSA below the median. A PSA level above the median identified 90% and 75% of cases diagnosed more than 2 and 10 years after blood draw, respectively. The associations were significantly greater for Gleason ≤7 versus 8+ disease. At 10+ years, the association of prostate cancer with PSA was comparable with that with the PRS [OR per SD increase: 1.88 (1.45–2.46) and 2.12 (1.55–2.93), respectively]. Conclusions: We found PSA to be an informative marker of prostate cancer risk at least a decade before diagnosis across multiethnic populations. This association was diminished with increasing time, greater for low grade tumors, and comparable with a PRS when measured 10+ years before diagnosis. Impact: Our multiethnic investigation suggests broad clinical implications on the utility of PSA and PRS for risk stratification in prostate cancer screening practices.