ContextProstate‐specific antigen (PSA) testing increases prostate cancer diagnoses and reduces long‐term disease‐specific mortality, but also results in overdiagnoses and treatment‐related harms.ObjectiveTo systematically assess the benefits and harms of population‐based PSA screening and the potential net benefit to inform health policy decision‐makers in Germany.Evidence AcquisitionWe performed a protocol‐guided comprehensive literature search according to the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) statement. All steps were performed by one or two investigators; any discrepancies were resolved by consensus. To allow subgroup analyses for identifying the optimal screening parameters, the eight national trials conducted under the umbrella of the European Randomised study of Screening for Prostate Cancer (ERSPC) were included as individual trials.Evidence SynthesisWe included a total 11 randomised controlled trials (RCTs) with a total of 416 000 study participants. For all‐cause mortality, we found neither benefit nor harm. PSA screening was associated with a reduced risk of both prostate cancer mortality and the development of metastases. For the outcomes of health‐related quality of life, adverse effects and the consequences of false‐negative screening results there was no difference; however, this was due to the lack of eligible RCT data. Finally, PSA screening was associated with large numbers of overdiagnoses with adverse downstream consequences of unnecessary treatment (e.g. incontinence, erectile dysfunction) and large numbers of false‐positive PSA tests leading to biopsies associated with a small but not negligible risk of complications. Limitations of this assessment include the clinical heterogeneity and methodological limitations of the underlying studies.ConclusionsThe benefits of PSA‐based prostate cancer screening do not outweigh its harms. We failed to identify eligible screening studies of newer biomarkers, PSA derivatives or modern imaging modalities, which may alter the balance of benefit to harm.Patient SummaryIn the present study, we reviewed the evidence on the PSA blood test to screen men without symptoms for prostate cancer. We found that the small benefits experienced by some men do not outweigh the harms to many more men.