Background: MRI of the prostate may improve diagnostic accuracy of prostate cancer. Different fusion approaches with transrectal ultrasound images are employed. Objective: To determine the detection rate of prostate cancer in men undergoing transperineal template-guided saturation biopsy (TTSB) with MRI-based cognitive fusion. Methods: Between the years 2010-2015, 164 consecutive men underwent a multiple-core prostate TTSB. Univariable and multivariable logistic regression analyses were used to address the relationship between clinical TTSB parameters and prostate cancer detection rate. Covariates consisted of age, prostate-specific antigen (PSA), prostate volume, PSA density, digital rectal examination findings, existence of suspicious prostate lesions on MRI, number of previous negative biopsy sets, and number of cores taken during TTSB. Results: Mean age was 65 years and mean PSA was 14 ng/ml, mean prostate volume was 63 ml. Seventy percent of patients had at least two previous negative transrectal biopsy series and another 19% had at least one negative biopsy. One-hundred and fourteen patients (70%) underwent prostate MRI prior to the biopsy. The detection rate of prostate cancer among these patients was 46% of which 69% had Gleason score ≥ 7. Men with a suspicious lesion on MRI (n=80) had a detection rate of 50%, compared to 33% in patients with negative MRI study. On multivariate analysis, the most significant independent predictive factor was PSA density (p= 0.001). Other nearly significant parameters were suspicious MRI lesion, prostate volume and suspicious digital examination. Of note, the prostate cancer detection rate among patients with no MRI study prior to TTSB was 26%. Conclusions: Utilizing MRI cognitive fusion approach increases the detection rate of clinically significant prostate cancer (Gleason score ≥ 7). In patients with existing suspicion for prostate cancer after multiple negative standard TRUS-guided biopsies, performing TTSB after taking into consideration the findings on MRI and PSA density will increase dramatically the detection rate of significant disease.