The objective of this study is to prospectively determine whether multiparametric MRI (mpMRI) based staging is more accurate independent predictor of outcome than traditional clinical variables in patients treated with brachytherapy (BT) and external beam radiotherapy (EBRT). In September 2010 we launched a prospective study of mpMRI guided High-Dose-Rate (HDR) BT (15 Gy) and supplemental EBRT (37.5 Gy). Inclusion criteria included localized intermediate or high-risk prostate cancer, patients with seminal vesicle invasion (SVI) extension >1cm or positive pelvic nodes were excluded. The primary endpoints were biochemical (nadir +2 ng/mL) and metastatic failure. Clinical variables included baseline PSA value, clinical T-stage, Gleason score, percentage of positive cores on prostate biopsy, use of hormonal therapy, MRI T-stage, risk-group based on clinical T-stage and risk-group based on MRI T-stage. Descriptive, univariate and multivariate Cox analyses were performed. Cumulative hazard rate function was estimated through the Nelson-Aalen method in order to describe the cumulative risk of the events of interest. Univariate and multivariate hazard ratios were obtained from proportional hazards Cox regression models. Log-rank tests were used to compare hazards across categories of MRI-based T stages. One hundred eighty-five patients had been prospectively treated (123 high-risk and 62 intermediate-risk). Median age was 71 years (range 56-82); 20.5% had MR T-stage T1-T2b, 37.3% T2c, 31% T3a and 11.2% T3b; 22.2% Gleason 6, 49.5% Gleason 7 and 28.2% Gleason 8-10; and median baseline PSA was 11.7 ng/mL (2.9–153). Median follow-up was 46 months (range 16-70). At the time of the current analysis, 15 (8.1%) patients had a biochemical failure and 9 (4.9%) had developed distant metastases. None of the traditional clinical variables (PSA, Gleason, and clinical stage) predicted for biochemical or metastatic failure. The 5-year cumulative risk of biochemical failure for patients with MRI-T1/T2 stage and MRI-T3 stage were 5% (95% CI 1.5-16) and 30.2% (95% CI 15.9-57.4) respectively. The 5-year cumulative risk of metastatic failure was 2% (95% CI 0.2-14) and 18.4% (95% CI 8.3-40.6) respectively. Multivariate Cox analysis demonstrated that the only independent predictor of biochemical failure was SVI on mpMRI (HR 12.7, 95% CI 2.9–55.7; P = 0.001). The two independent predictors of metastatic failure were SVI (HR 19.3, 95% CI 1.9-193.9; P = 0.012) and the percentage of positive cores on prostate biopsy (HR 10.4, 95% CI 1.2-88.6; P = 0.032). Pretreatment mpMRI findings are more accurate independent predictors of outcome than clinical variables, and in particular, the presence of extracapsular extension (T3a), SVI (T3b) and higher percentage of positive cores on biopsy predict a worse prognosis.