Prostate cancer is a heterogeneous disease, and risk stratification systems have been proposed to guide treatment decisions. However, significant heterogeneity remains for those with unfavorable-risk disease.This study included 3335 patients undergoing radical prostatectomy without adjuvant radiotherapy in the SEARCH database. High-risk patients were dichotomized into standard and very high-risk (VHR) groups based on primary Gleason pattern, percentage of positive biopsy cores (PPBC), number of NCCN high-risk factors, and stage T3b-T4 disease. Similarly, intermediate-risk prostate cancer was separated into favorable and unfavorable groups based on primary Gleason pattern, PPBC, and number of NCCN intermediate-risk factors.Median follow-up was 78 months. Patients with VHR prostate cancer had significantly worse PSA relapse-free survival (PSA-RFS, P < 0.001), distant metastasis (DM, P = 0.004), and prostate cancer-specific mortality (PCSM, P = 0.015) in comparison to standard high-risk (SHR) patients in multivariable analyses. By contrast, there was no significant difference in PSA-RFS, DM, or PCSM between SHR and unfavorable intermediate-risk (UIR) patients. Therefore, we propose a novel risk stratification system: Group 1 (low-risk), Group 2 (favorable intermediate-risk), Group 3 (UIR and SHR), and Group 4 (VHR). The c-index of this new grouping was 0.683 for PSA-RFS and 0.800 for metastases, compared to NCCN-risk groups which yield 0.666 for PSA-RFS and 0.764 for metastases.Patients classified as VHR have markedly increased rates of PSA relapse, DM, and PCSM in comparison to SHR patients, whereas UIR and SHR patients have similar prognosis. Novel therapeutic strategies are needed for patients with VHR, likely involving multimodality therapy.