wnloade pose: The relationship between prostate-specific antigen (PSA) level and prostate cancer risk resubject to fundamental disagreements. We hypothesized that the risk of prostate cancer on biopsy iven PSA level is affected by identifiable characteristics of the cohort under study. erimental Design: We used data from five European and three U.S. cohorts of men undergoing y for prostate cancer; six were population-based studies and two were clinical cohorts. The associbetween PSA and prostate cancer was calculated separately for each cohort using locally weighted plot smoothing. ults: The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities en cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the rve. These disparities were associated with identifiable differences between cohorts: for a given PSA a greater number of biopsy cores increased the risk of cancer (odds ratio for >6versus 6-core bi1.35; 95% confidence interval, 1.18-1.54; P < 0.0005); recent screening led to a smaller increase in er unit change in PSA (P = 0.001 for interaction term) and U.S. cohorts had higher risk than the ean cohorts (2.14; 95% confidence interval, 1.99-2.30; P < 0.0005). clusions: Our results suggest that the relationship between PSA and risk of a positive prostate biaries, both in terms of the probability of prostate cancer at a given PSA value and the shape of the opsy v risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated. Clin Cancer Res; 16(17); 4374–81. ©2010 AACR.