Objective To study the use of a baseline prostate-specific antigen (PSA) and digital rectal examination in men (aged 40-49 years) in predicting long-term prostate cancer risk in a prospectively followed, representative population cohort. Patients and Methods Since 1990, a random sample of men in Olmsted County (aged 40-49 years) has been followed up prospectively (n = 268), with biennial visits, including a urologic questionnaire, PSA screening, and physical examination. The ensuing risk of prostate cancer (CaP) was compared using survival analyses. Results Median follow-up was 16.3 years (interquartile range 14.0-17.3, max 19.1). For men with a baseline PSA <1.0 ng/mL (n = 195), the risk of subsequent Gleason 6 CaP diagnosis by 55 years was 0.6% (95% confidence interval [CI] 0%-1.7%) and 15.7% (95% CI 6.5%-24.9%) for men with a baseline PSA ≥1.0 ng/mL. No man with a low baseline PSA developed an intermediate or high risk CaP, whereas 2.6% of men with a higher baseline PSA did (95% CI 0.58%-4.6%). Conclusion Men (aged 40-49 years) can be stratified with a baseline PSA. If it is below 1.0 ng/mL, there is very little risk for developing a lethal CaP, and as many as 75% of men might be able to avoid additional PSA screening until 55 years. Conversely, men aged 40-49 years with a baseline PSA level >1.0 ng/mL had a significant risk of CaP diagnosis and should be monitored more closely.