OBJECTIVE: To compare the diagnostic performance of systematic prostate biopsy schemes in men scheduled for biopsy due to suspected prostate cancer. DESIGN: Systematic review DATA SOURCES: Electronic databases, reference lists of included studies, relevant urological journals, and experts. REVIEW METHODS: We included studies that compared the cancer yield of a systematic prostate biopsy scheme (index test) with any systematic reference scheme in the same population of men. We excluded studies that did not compare the tests in the same population, non-systematic biopsies, and computer simulation studies. The primary measure of comparison between index test (in general the standard sextant scheme) and reference test was the relative positivity rate (RPR) of the index test. We pooled data using a random effects model, where appropriate. RESULTS: Eighty-seven studies with 20,698 patients were analysed. The standard sextant scheme had a significantly lower cancer yield than most of the more extensive biopsy schemes. Adding laterally directed cores increased the yield significantly, whereas additional transition zone cores did not. Schemes with 18 and more cores of the 5-region pattern showed the highest cancer yield (RPR 1.48; 95%-CI 1.32-1.66). However, the difference in the cancer yield of this scheme to the yield of the 12- core scheme from pattern ‘mid-lobar peripheral zone + lateral peripheral zone’ (RPR 1.31; 95%-CI 1.25-1.37) and the 10-core scheme of the 5-region pattern (RPR 1.38; 95%-CI 1.08-1.76) was not statistically significant. While some evidence suggests that adverse events for schemes up to 12 cores are similar to those of the sextant pattern, this remains unclear for more extended schemes. CONCLUSIONS: Schemes, which apply additional laterally directed cores, showed a higher cancer yield. It still has to be demonstrated that extended biopsy schemes with a higher cancer yield do lead to a survival benefit due to early cancer detection.