© 2016 Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States. Background: Use of magnetic resonance (MR) imaging to improve prostate biopsy efficiency is rapidly gaining in popularity. The aim of this study was to assess the biopsy efficiency of MR/ultrasound (MR/US) fusion-guided ("targeted") biopsies vs extended-sextant 12-core ("standard") biopsies for overall and high-grade prostate cancer detection. Methods: From August 2007 to February 2014, 1003 men were enrolled in a prospective trial comparing the diagnostic yield of targeted and standard prostate biopsies performed during the same session. A total of 17 619 biopsy cores were reviewed. Biopsy efficiency was determined by dividing the total number of cores by the number of positive cores obtained. All statistical tests were two-sided. Results: A mean of 12.3 (95% confidence interval [CI] = 12.2 to 12.3) standard and 5.3 (95% CI = 5.1 to 5.5) targeted biopsy cores were obtained from each patient. Targeted biopsy detected 461 cases of prostate cancer, of which 173 (37.5%) were high grade (Gleason score ≥ 4 + 3), while standard biopsy detected 469 cases of prostate cancer, of which 122 (26.5%) were high grade. The percentage of biopsy cores positive for prostate cancer, irrespective of grade, was statistically significantly higher for targeted than for standard biopsies (27.9% vs 13.5%, respectively, P <. 001), with 11.5 targeted cores vs 26.2 standard cores utilized per diagnosis of prostate cancer. For detection of high-grade cancer, 30.7 targeted vs 100.8 standard cores were utilized per diagnosis. Conclusion: In men with MR-visible prostate lesions, targeted biopsy is more efficient than standard biopsy, diagnosing a similar number of cancer cases and more high-grade cases while sampling 56.1% fewer biopsy cores.