Background: Currently there is little data to guide the use of testosterone replacement therapy in prostate cancer patients who have received radiation therapy (RT). We sought to evaluate the impact of post-RT testosterone replacement on prostate cancer outcomes in a large national cohort. Methods: We conducted a population-based cohort study using the Veterans Affairs Informatics and Computing Infrastructure. We identified node-negative and non-metastatic prostate cancer patients diagnosed between 2001-2015 treated with RT. We excluded patients for missing covariate and follow-up data. Receipt of testosterone was coded as a time-dependent covariate. Other covariates included: age, Charlson Comorbidity index, diagnosis year, body mass index, race, PSA, clinical T/N/M stage, Gleason score, and receipt of hormone therapy. We evaluated prostate cancer-specific survival, overall survival, and biochemical recurrence free survival using multivariable Cox regression. Results: Our cohort included 41,544 patients, of whom 544 (1.3%) received testosterone replacement after RT. There were no differences in Charlson comorbidity, clinical T stage, median pre-treatment PSA or Gleason score between treatment groups. Testosterone patients were more likely to be of younger age, non-black, have a lower median post-treatment PSA nadir (0.1 vs. 0.2; p < 0.001), have higher BMI, and have used hormone therapy (46.7% vs 40.3%; p = 0.003). Median duration of ADT usage was equivalent between treatment groups (testosterone: 185 days vs. non-testosterone: 186 days, p = 0.77). The median time from RT to TRT was 3.52 years. After controlling for differences in covariates between treatment groups, we found no difference in prostate cancer specific mortality (HR 1.02; 95% CI 0.62-1.67; p = 0.95), overall survival (HR 1.02; 95% CI 0.84-1.24; p = 0.86), non-cancer mortality (HR 1.02; 95% CI 0.82-1.27; p = 0.86) biochemical recurrence free survival (HR 1.07; 95% CI 0.90-1.28; p = 0.45). Conclusions: Our results suggest that testosterone replacement is safe in prostate cancer patients who have received RT. Prospective data are required to confirm the safety of post-RT testosterone replacement.