Objectives: To investigate the relationship between diabetes and metformin use with outcomes after radical prostatectomy (RP) for clinically localized cancer. Methods: A total of 112 diabetic metformin users and 98 diabetic nonmetformin users treated with RP from 1990 to 2009 were identified. Nondiabetic controls were match using their 5-year risk of biochemical recurrence (BCR) as calculated by the preoperative Kattan nomogram. Results: A total of 616 patients were evaluated in this study. There was no significant difference between nondiabetic and diabetic patients, including metformin users, with respect to age, clinical stage, preoperative prostate-specific antigen (PSA) score, pathologic Gleason score, and pathologic stage. Diabetic patients, including metformin users, were more likely to be of African American or Hispanic background than were nondiabetic controls (P = .001). The estimated 5-year BCR-free survival was 75.0% for nondiabetic patients, compared with 66.1% for metformin users and 59.3% for diabetic nonmetformin users (P = .004). In multivariate analysis, metformin use was not significantly associated with risk of BCR (HR = 0.94; 95% CI = 0.6-1.5, P = .817). However, being diabetic, regardless of metformin use, resulted in a 55% increase in risk of BCR (HR = 1.55; 95% CI = 1.03-2.33, P = .034). Conclusions: Diabetes, regardless of metformin use, was significantly associated with an increased likelihood of BCR after RP. Metformin use did not prove to be of any benefit. These observations underscore the importance for further studies evaluating the metabolic pathways that affect prostate cancer biology.