Prostate cancer alters cellular metabolism through events potentially preceding cancer morphological formation. Magnetic resonance spectroscopy (MRS)-based metabolomics of histologically-benign tissues from cancerous prostates can predict disease aggressiveness, offering clinically-translatable prognostic information. This retrospective study of 185 patients (2002-2009) included prostate tissues from prostatectomies (n = 365), benign prostatic hyperplasia (BPH) (n = 15), and biopsy cores from cancer-negative patients (n = 14). Tissues were measured with high resolution magic angle spinning (HRMAS) MRS, followed by quantitative histology using the Prognostic Grade Group (PGG) system. Metabolic profiles, measured solely from 338 of 365 histologically-benign tissues from cancerous prostates and divided into training-testing cohorts, could identify tumor grade and stage, and predict recurrence. Specifically, metabolic profiles: (1) show elevated myo-inositol, an endogenous tumor suppressor and potential mechanistic therapy target, in patients with highly-aggressive cancer, (2) identify a patient sub-group with less aggressive prostate cancer to avoid overtreatment if analysed at biopsy; and (3) subdivide the clinicopathologically indivisible PGG2 group into two distinct KaplanMeier recurrence groups, thereby identifying patients more at-risk for recurrence. Such findings, achievable by biopsy or prostatectomy tissue measurement, could inform treatment strategies. Metabolomics information can help transform a morphology-based diagnostic system by invoking cancer biology to improve evaluation of histologically-benign tissues in cancer environments.The utility of the serum prostate specific antigen (PSA) screening test is now well established, both by its capacity to reveal early-stage disease and its discovery of almost all newly-detected prostate cancers 1-3 . However, despite being prostate-specific, PSA testing is not cancer-specific. Current medical imaging detects 44-87% 4 of clinically significant cancers but remains challenged by small lesions. For this reason, prostate cancer (PCa) diagnoses are still only positively confirmed by prostate transrectal biopsies, performed after an elevated PSA result. After a positive biopsy, an initial cancer grade is assigned according to histological analysis of the biopsy cores; this grade will help determine whether the prostate should be surgically removed by prostatectomy or the patient should enter active surveillance. If a prostatectomy is performed, histological examination of the entire prostate will determine the pathological stage of the disease. With this information, follow-up therapies can be recommended, if warranted.Statistics on prostate cancer's natural history suggest that >70% of patients diagnosed after PSA screening are likely to experience an indolent disease course that little impacts their well-being. About 17% of these newly PSA-diagnosed patients, however, will confront an aggressive prostate cancer that significantly impairs function