Objective: To evaluate the comparative effectiveness of local vs systemic therapy among patients diagnosed with nonmetastatic clinical T4 prostate cancer. Methods: Using the National Cancer Database men with clinical T4N0-1M0 prostate cancer from 2004 to 2013 were identified. Local therapy was defined as radiation (RT with androgen deprivation therapy [ADT]), surgery (radical prostatectomy with ADT), or combined radiation plus surgery (radical prostatectomy plus RT with ADT). Systemic therapy was defined as ADT or chemotherapy alone. The primary outcome of overall survival was estimated using the Kaplan-Meier method. Factors associated with overall survival were determined by Cox proportional hazards models. Results: A total of 1914 patients were included in our analysis, 1559 received local therapy and 355 received systemic therapy. Median 5-year survival for local vs systemic therapy was 41.5 and 28.2 months, respectively. On multivariable analysis, local therapy was associated with increased overall survival compared to systemic therapy (hazard ratio [HR] = 0.52; 95% confidence interval [CI] 0.44-0.62, P <.001). Comparing local therapy treatment modalities, both radiation (HR = 0.44; 95% CI 0.36-0.53, P <.001) and surgery (HR = 0.67; 95% CI 0.55-0.82, P <.001) were associated with increased overall survival compared to systemic therapy. Among those receiving local therapy, more patients were treated with radiation (n = 709/1559 or 45.5%) compared to surgery (n = 560/1559 or 35.9%) or combined radiation plus surgery (n = 290/1559 or 18.6%) with 5-year overall survival by treatment type being 61%, 51.4%, and 62.2%, respectively. Conclusion: Local therapy for clinical T4 prostate cancer is associated with improved overall survival. Due to the retrospective, nonrandomized nature of the study design, a clinical trial is needed to better define the efficacy of local therapy in this high-risk patient population.