Purpose To evaluate the cost-effectiveness of multiparametric diagnostic magnetic resonance (MR) imaging examination followed by MR imaging-guided biopsy strategies in the detection of prostate cancer in biopsy-naive men presenting with clinical suspicion of cancer for the first time. Materials and Methods A decision-analysis model was created for biopsy-naive men who had been recommended for prostate biopsy on the basis of abnormal digital rectal examination results or elevated prostate-specific antigen levels (age groups: 41-50 years, 51-60 years, and 61-70 years). The following three major strategies were evaluated: (a) standard transrectal ultrasonography (US)-guided biopsy; (b) diagnostic MR imaging followed by MR imaging-targeted biopsy, with no biopsy performed if MR imaging findings were negative; and (c) diagnostic MR imaging followed by MR imaging-targeted biopsy, with a standard biopsy performed when MR imaging findings were negative. The following three MR imaging-guided biopsy strategies were further evaluated in each MR imaging category: (a) biopsy with cognitive guidance, (b) biopsy with MR imaging/US fusion guidance, and (c) in-gantry MR imaging-guided biopsy. Model parameters were derived from the literature. The primary outcome measure was net health benefit (NHB), which was measured as quality-adjusted life-years (QALYs) gained or lost by investing resources in a new strategy compared with a standard strategy at a willingness-to-pay (WTP) threshold of $50 000 per QALY gained. Probabilistic sensitivity analysis was performed by using Monte Carlo simulations. Results Noncontrast MR imaging followed by cognitively guided MR biopsy (no standard biopsy if MR imaging findings were negative) was the most cost-effective approach, yielding an additional NHB of 0.198 QALY compared with the standard biopsy approach. Noncontrast MR imaging followed by in-gantry MR imaging-guided biopsy (no standard biopsy if MR imaging findings were negative) led to the highest NHB gain of 0.251 additional QALY compared with the standard biopsy strategy. All MR imaging strategies were cost-effective in 94.05% of Monte Carlo simulations. Analysis by age groups yielded similar results. Conclusion MR imaging-guided strategies for the detection of prostate cancer were cost-effective compared with the standard biopsy strategy in a decision-analysis model. © RSNA, 2017 Online supplemental material is available for this article.