Purpose: Patients with negative transrectal ultrasound biopsies and a persistent clinical suspicion are at risk for occult but significant prostate cancer. The ability of multiparametric magnetic resonance imaging/ultrasound fusion biopsy to detect these occult prostate lesions may make it an effective tool in this challenging scenario. Materials and Methods: Between March 2007 and November 2011 all men underwent prostate 3 T endorectal coil magnetic resonance imaging. All concerning lesions were targeted with magnetic resonance imaging/ultrasound fusion biopsy. In addition, all patients underwent standard 12-core transrectal ultrasound biopsy. Men with 1 or more negative systematic prostate biopsies were included in our cohort. Results: Of the 195 men with previous negative biopsies, 73 (37%) were found to have cancer using the magnetic resonance imaging/ultrasound fusion biopsy combined with 12-core transrectal ultrasound biopsy. High grade cancer (Gleason score 8-) was discovered in 21 men (11%), all of whom had disease detected with magnetic resonance imaging/ultrasound fusion biopsy. However, standard transrectal ultrasound biopsy missed 12 of these high grade cancers (55%). Pathological upgrading occurred in 28 men (38.9%) as a result of magnetic resonance imaging/ultrasound fusion targeting vs standard transrectal ultrasound biopsy. The diagnostic yield of combined magnetic resonance imaging/ultrasound fusion platform was unrelated to the number of previous negative biopsies and persisted despite increasing the number of previous biopsy sessions. On multivariate analysis only prostate specific antigen density and magnetic resonance imaging suspicion level remained significant predictors of cancer. Conclusions: Multiparametric magnetic resonance imaging with a magnetic resonance imaging/ultrasound fusion biopsy platform is a novel diagnostic tool for detecting prostate cancer and may be ideally suited for patients with negative transrectal ultrasound biopsies in the face of a persistent clinical suspicion for cancer. © 2012 AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.