INTRODUCTION: Magnetic resonance imaging (MRI) is being more widely used in the detection of prostate cancer (PCa), particularly after an initial negative biopsy. In this study, we compared 12-core systematic biopsy (SYS), MRI-targeted biopsy (TAR), and the association of systematic and MRI-targeted (SYS+TAR) prostate biopsy in patients with previous biopsy and those who were biopsy-naive to evaluate the differences in terms of cancer detection and clinically significant cancer detection between the three modalities. METHODS: Overall, 203 consecutive patients with suspicion of PCa were analyzed; 48.2% were biopsy-naive and 51.7% had at least one previous negative prostate biopsy. The median age was 66 years, median prostate-specific antigen (PSA) level was 7.9 ng/mL and median prostate volume was 46 mL. 38.9% had SYS, 19.2% TAR only, and 41.8% had SYS+TAR biopsy. RESULTS: Overall, the PCa detection (PCaDR) was 63%. The SYS+TAR biopsy detected significantly more cancer than SYS and TAR only biopsies (72.9% vs. 56.9% and 53.8% respectively; p=0.03). Detection rate of clinically significant cancer (csPCaDR) was 50.7% overall; 65.8% in the SYS+TAR biopsy vs. 39.2% in the SYS and 48.7% in the TAR groups (p=0.002). In the biopsy-naive group, PCaDR and csPCaDR were significantly higher in the SYS+TAR group than in the SYS and TAR groups (p=0.01). In the repeat biopsy group, PCaDR and csPCaDR were equivalent in the TAR and SYS+TAR groups and higher than in the SYS group (p=0.001). CONCLUSIONS: TAR biopsy, when added to SYS biopsy, was associated with a higher detection rate of csPCa in biopsy-naive patients when compared to TAR and SYS only biopsies. In patients after previous negative biopsy, detection rates of csPCa were equivalent for SYS+TAR and TAR only biopsies, but higher than SYS.