Objective To better assess the increased utilization of multiparametric magnetic resonance imaging (mpMRI) and fusion biopsy of the prostate, we compared prostate cancer detection rates among (a) men undergoing MR-ultrasound (US) fusion biopsy, (b) mpMRI cognitive-registration biopsy, and (c) conventional transrectal US-guided biopsy for the detection of prostate cancer. Materials and Methods We present a retrospective review of consecutive patients undergoing mpMRI of the prostate with subsequent prostate biopsy from October 2013 to September 2015. Lesions concerning for prostate cancer visualized on mpMRI were targeted with cognitive-registration or MR-US fusion biopsies. A cohort of men undergoing conventional prostate biopsy was utilized for comparison. Rates of cancer detection were compared among the 3 cohorts. Results A total of 231 patients underwent mpMRI-targeted biopsy (81 fusion, 150 cognitive). There was no difference in prostate specific antigen, mpMRI-defined Prostate Imaging Reporting and Data System score or number of lesions, or history of prostate cancer among the cohorts. The overall detection rate of cancer was significantly higher in the fusion cohort (48.1%) compared with both the cognitive (34.6% P  = .04) and conventional (32.0%, P  = .03) cohorts. Cancer detection rates were comparable in the MRI-cognitive and transrectal prostate US biopsy groups (34.6% vs 32%). MR fusion detected significantly more Gleason ≥7 cancer (61.5 vs 37.5%, P  = .04) and significantly less Gleason 6 cancer (38.5 vs 62.5%, P  = .04) compared with conventional biopsy. Conclusion Targeted biopsy of the prostate using MR-US fusion increased the cancer detection rate compared with both cognitive registration and conventional biopsy and was associated with detection of higher-grade cancer compared with conventional biopsy.