Background: The value of prostate-specific antigen velocity (PSAV) in screening for prostate cancer (PCa) and especially for clinically significant PCa is unclear. Objective: To assess the value of PSAV in screening for PCa. Specifically, the role of PSAV in lowering the number of unnecessary biopsies and reducing the detection rate of indolent PCa was evaluated. Design, Setting, and Participants: All men included in the study cohort were participants in the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam section. Intervention: During the first and second screening round, a PSA test was performed on 2217 men, and all underwent a biopsy during the second screening round 4 yr later. Measurements: PSAV was calculated and biopsy outcome was classified as benign, possibly indolent PCa, or clinically significant PCa. Results and Limitations: A total of 441 cases of PCa were detected, 333 were classified as clinically significant and 108 as possibly indolent. The use of PSAV cut-offs reduced the number of biopsies but led to important numbers of missed (indolent and significant) PCa. PSAV was predictive for PCa (OR: 1.28, p < 0.001) and specifically for significant PCa (OR: 1.46, p < 0.001) in univariate analyses. However, multivariate analyses using age, PSA, prostate volume, digital rectal examination and transrectal ultrasonography outcome, and previous biopsy (yes/no) showed that PSAV was not an independent predictor of PCa (OR: 1.01, p = 0.91) or significant PCa (OR: 0.87, p = 0.30). Conclusions: The use of PSAV as a biopsy indicator would miss a large number of clinically significant PCa cases with increasing PSAV cut-offs. In this study, PSAV was not an independent predictor of a positive biopsy in general or significant PCa on biopsy. Therefore, PSAV does not improve the ERSPC screening algorithm. (c) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.