Both the incidence of, and the mortality due to, prostate cancer in the USA are higher in African-American men than in Caucasian men. This is particularly true in men less than 60 years of age. Our findings indicate that both the prevalence and the extensiveness of high-grade prostatic intraepithelial neoplasia (PIN) are higher in African-American men compared to Caucasians and that this discrepancy starts as early as the third decade of life. In an autopsy series comprising 650 men, extensive high-grade PIN with diffuse involvement of the prostate gland was evident in 25 (7%) of 364 African-American men less than 50 years of age compared to 4 (2%) of 208 Caucasian men in the same age group (p = 0.002). In a series of more than 1,200 men undergoing radical prostatectomy for clinically localized prostate cancer, extensive high-grade PIN was significantly and consistently higher in the African-American cohort than the Caucasian cohort. The difference was more evident in younger patients and those with smaller, organ-confined tumors. In a subset of 216 men (71 African-Americans and 138 Caucasians) with clinical stage T1C prostate cancer, extensive high-grade PIN was identified in 33% and 12% of the two groups respectively (p = 0.001). Moreover, in patients with organ-confined disease, both Gleason score and the extensiveness of high-grade PIN were significant predictors of biochemical recurrence. Our findings suggest an important role for high-grade PIN in the development of clinically significant, potentially aggressive prostate cancer in African-American men. In this epidemiologically identifiable high-risk group, there is a potential opportunity for chemoprevention strategies in younger men with high-grade PIN.