Background: Prostate-specific antigen (PSA) measurement after definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for localized prostate cancer (PC) has been proposed as an early prognostic biomarker. We investigate the association between 3-month post-RT PSA and biochemical progression-free survival (bPFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Methods: We identified 5,783 patients with intermediate- or high-risk localized PC diagnosed between 2000-2015 and treated with RT and ADT from Veterans Affairs data. Patients were divided into groups based on 3-month post-RT PSA values: < 0.10 ng/mL, 0.10-0.49 ng/mL, and ≥0.50 ng/mL. The effect of 3-month PSA group on bPFS, PCSS, and OS were evaluated in multivariable Cox models adjusting for potential confounders. Results: There were 2,651 intermediate risk and 3,132 high risk patients; 11% had a 3-month PSA of ≥0.50 ng/mL. Higher 3-month PSA was strongly associated with each outcome; compared to the < 0.10 ng/mL group, we noted greater hazards for the 0.10-0.49 ng/mL group (HR for bPFS: 2.41, p < 0.001; PCSS: 2.29, p < 0.001; OS: 1.21, p = 0.003) and the ≥ 0.50 ng/mL group (HR for bPFS: 5.23; PCSS: 3.97; OS: 1.50; p < 0.001 for all). When analyzed separately, 3-month PSA group was predictive of OS in the high-risk group (p < 0.001) but not the intermediate-risk group (p = 0.21). Conclusions: 3-month post-RT PSA is a strong prognostic biomarker for bPFS and PCSS in patients with intermediate and high-risk PC, and OS in patients with high-risk PC. 3-month PSA measurement may augment clinical decision-making and holds promise as a potential surrogate endpoint in clinical trials.