Background: The US Preventive Services Task Force recommended against prostate-specific antigen (PSA) screening for prostate cancer based primarily on 2 large long-term randomized-controlled trials (RCTs) and a systematic review of harms resulting from screening. Objective: To support use of large, long-term randomized trials as the evidence base for clinical guidelines on screening and to draw attention to limitations of modeling studies used for this purpose. Methods: We respond to critiques of use of RCTs as the primary evidence base, considering the results of the Prostate, Lung, Colorectal and Ovarian (PLCO) and European Randomized Study of Screening for Prostate Cancer (ERSPC) trials, documented harms resulting from PSA screening, and methodological concerns with modeling studies. Results: The PLCO and ERSPC provided 11–13 years of follow-up on over 250,000 subjects. The PLCO, despite limitations, is most representative of US populations, screening and treatment practices, and showed no mortality benefit resulting from annual PSA testing after 13 years of follow-up. The confidence interval was narrow and precluded more than a 13% relative mortality reduction. Competing causes of mortality in older men make it progressively less likely that longer follow-up will demonstrate a large absolute reduction in disease-specific mortality. With continued screening, the increasing prevalence of asymptomatic cancers in older men will increase the rate of overdiagnosis. Potential harms from screening and treatment are significant. Conclusions: Projections from models are subject to mistaken assumptions and investigator biases, and should not be accorded the same weight as evidence from RCTs. Current empiric evidence is sufficient to support the US Preventive Services Task Force guideline that clinicians should recommend against PSA screening for prostate cancer.