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BACKGROUND The use of a magnetic resonance imaging (MRI)-directed diagnostic pathway in men at first prostate cancer work-up has been introduced within European prostate cancer guidelines. Differences in MRI-directed pathway yields need elaboration. OBJECTIVE To investigate the diagnostic yields of MRI-directed diagnostic pathways in biopsy-naïve men suspected of having prostate cancer. DESIGN, SETTING, AND PARTICIPANTS This analysis uses the data of the Cochrane diagnostic test accuracy systematic review on the utility of prostate MRI and MRI-targeted biopsy for significant disease in men at first diagnosis. The paired agreement analysis data were reformulated for five unique biopsy strategies focusing on diagnostic yields and biopsy avoidance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Significant prostate cancer was defined as International Society of Urological Pathology (ISUP) grade group ≥2. RESULTS AND LIMITATIONS The detection-focused pathway maximises the detection of significant disease (28% [95% confidence interval {CI} 24-34%]), while not reducing biopsy or core numbers, or the overdiagnoses of insignificant cancers (21% [18-25%]). The triage-focused pathway omits systematic biopsy use (reduction of 100%) and thereby reduces overdiagnoses of ISUP grade group 1 cancers (to 14% [11-17%]), but compromises the detection of significant disease (23% [19-28%]). The MRI-focused pathway maximises the detection of significant disease in MRI-positive men at a cost of nondetection of significant disease in MRI-negative men, thus reducing biopsies and overdiagnoses of ISUP grade 1 (strategy proposed by European Association of Urology guidelines). CONCLUSIONS All MRI-directed biopsy pathways have beneficial outcomes compared with conventional systematic biopsy, with potentially reduced risks and harms. MRI-directed biopsy management as the default strategy optimises diagnostic yields in men at first diagnosis and may be the only test required in a significant proportion. Deploying additional systematic biopsy depends on balancing risks and benefits according to clinical care priorities. PATIENT SUMMARY High-quality data on magnetic resonance imaging (MRI)-based prostate cancer diagnosis suggests that MRI-directed pathways are better than standard systematic biopsies in making correct diagnoses of important prostate cancers in men presenting for the first time with suspected cancer. MRI-directed diagnostics should be backed up by a systematic biopsy in selected men, according to MRI findings and patient risk profiles.