Background: Despite evidence of prolonged survival when adding androgen deprivation therapy (ADT) to external beam radiation therapy (EBRT) in men with unfavorable intermediate- and high-risk prostate cancer (PC), some of these men are not receiving ADT. We explored whether comorbidity can explain this discrepancy given the observation that survival may be shortened in men with moderate to severe comorbidity who receive ADT. Methods: Between 10/1997 and 5/2013, 3,348 men with unfavorable intermediate- (2,380 patients; 70.7%) or high-risk (986 patients; 29.3%) PC were treated at the Prostate Cancer Foundation of Chicago using brachytherapy with or without neoadjuvant EBRT and/or ADT, and formed the study cohort. A multivariable logistic regression analysis was used to evaluate whether comorbidity (history of congestive heart failure [CHF] and/or myocardial infarction [MI]) was associated with decreased odds of ADT use in men with unfavorable intermediate- or high-risk PC, adjusting for age, PC prognostic factors, year of brachytherapy, and EBRT use. Results: Among patients with unfavorable-intermediate-risk PC, 31.2% received ADT, and in the high-risk cohort, 38.3%, 12.3%, and 4.8% received up to 6, >6-18, or >18 months of ADT respectively. In men with high-risk PC, a history of CHF/MI was not significantly associated with decreased odds of ADT use of any duration (all p values >0.71), but the odds of ADT use decreased over time (adjusted odds ratio (AOR) 0.87, 95% confidence interval (CI) [0.83,0.91], p<0.0001; AOR 0.93, 95% CI [0.87,0.99], p=0.023; AOR 0.92, 95% CI [0.83,1.01], p=0.089, for up to 6, >6-18, and >18 months respectively, with no ADT as the reference). Similarly, in men with unfavorable intermediate-risk PC, a history of CHF/MI was not significantly associated with decreased odds of ADT use (p=0.49), whereas the odds of ADT use decreased significantly over time (AOR 0.96, 95% CI [0.94,0.98], p=0.0009). Conclusions: While ADT use has decreased over time in men with unfavorable intermediate- and high-risk PC undergoing brachytherapy with or without supplemental EBRT, this decrease does not appear to be occurring in men with a history of CHF or MI.