Background: Patients with an elevated PSA but negative prostate biopsy present a diagnostic and management dilemma. We evaluated the capability of multi-parametric (MP) MRI and MRI-USG Fusion prostate biopsy to detect clinically significant (CS) prostate cancer in men who have had a prior negative 12-core standard biopsy. Methods: Between 12/2012 and 06/2015, 374 men with an indication for prostate biopsy underwent pre-biopsy mpMRI followed by 12-core standard trans-rectal mapping biopsy (Mbx) and MRI-Ultrasound fusion targeted biopsy (Tbx) of lesions identified on mpMRI. The combination of Mbx and Tbx, when both occurred, constitutes a fusion biopsy (Fbx). Men who underwent both Mbx with or without Tbx using the Artemis/Pro-Fuse system with a previous biopsy but no diagnosis of prostate cancer were included. Patients without a lesion on MRI underwent Mbx only. Maximum Gleason scores (GS) was assigned on a per patient basis with Mbx GS available for all patients in the cohort and Tbx GS available only for patients with a lesion visible on MP-MRI. CS cancer was defined as GS ≥ 3+4. GS per patient was compared by chi-square and McNemar’s test. Results: 138 men (mean age = 64.0, mean psa = 11.6) met inclusion criteria. Fbx cancer detection rate in this population was 42%. 17 men (12%) were missed by Mbx but picked up on Tbx. Of these 17 men, 13 had Gleason ≥ 7.In comparison, 15 men were missed by Tbx, but only 2 were Gleason ≥ 7. Tbx had a higher rate of detection of CS cancer than Mbx, but this did not reach statistical significance (86% vs 68%, p = 0.09). MRI suspicion level correlated with the detection of CS cancer (p = 0.012). None of the 20 men with a negative MRI had GS ≥ 7 cancer detected on Mbx. The number of prior negative biopsies was not related to the likelihood of finding CS cancer on Fbx (p = 0.47). Conclusions: MRI suspicion score predicts detection of CS prostate cancer when paired with MRI-USG Fbx of the prostate, with a negative MRI correlating with no evidence of CS cancer on biopsy. MRI is a biomarker in this population that may, with more corroborative data, allow for men with a negative MRI to avoid repeat biopsies.