Background: For men diagnosed with high-risk prostate cancer (HRPC), external beam radiotherapy (EBRT) plus androgen deprivation therapy (ADT) is a standard treatment approach. However, for men with moderate to severe baseline co-morbidities, there may not be an overall survival (OS) benefit to EBRT + ADT when compared to treatment with EBRT alone. We report co-morbidity-related OS for men included in the National Cancer Database who were diagnosed with HRPC and treated with EBRT + ADT or EBRT alone from 2004 to 2012. Methods: HRPC was defined as clinical stage T3a or Gleason score ≥ 8 or PSA ≥ 20 ng/ml, in accordance with National Comprehensive Cancer Network guidelines. Cases were limited to those that received EBRT and had 1) known ADT status, 2) baseline Charlson co-morbidity score (CCS) of 1 or more, and 3) documented survival outcome. The Kaplan-Meier method and log rank test were used to estimate the OS and difference between the treatment groups. Cox regression models were used to evaluate the effects of covariates on OS. Results: At median lengths of follow-up of 42.1 months (IQR, 24.4 – 67.9) for EBRT + ADT and 46.5 months (IQR, 27.5 – 70.4) for EBRT alone, there were 3,599 deaths (33.6%) and 1,049 deaths (25.5%) in the respective treatment groups (Log rank p< 0.001). In the EBRT + ADT treatment group, estimated median time to death was 8.5 years (95% CI 8.2-8.7) for men with CCS of 1 and 5.8 years (95% CI 5.4-6.2) for men with CCS of 2 (Log rank p< 0.001). On multivariate testing adjusted for income, insurance status, and treatment facility type there was a significant increase in the risk of death when men with CCS of 2 were compared to those with CCS of 1 (hazard ratio = 1.75, 95% CI 1.63-1.89, p< 0.001) There was no race-related increase in mortality when OS for black men was compared to that of non-Hispanic white men. Conclusions: Treatment with EBRT + ADT is associated with increased mortality when compared to EBRT alone for men with baseline co-morbidities. Among men treated with EBRT + ADT, greater number of co-morbidities is associated with decreased OS.