Background: Multiple randomized controlled trials (RCTs) have demonstrated the benefit of the addition of androgen deprivation therapy (ADT) to external beam radiotherapy (EBRT) in the treatment of men with localized prostate cancer (PC). Anti-androgens (AA) may have a better toxicity profile than luteinizing hormone-releasing hormone agonists (LHRHa). However, no RCT has directly compared these agents in combination with radical EBRT. We evaluated outcomes for men with localized PC treated with EBRT in conjunction with either LHRHa or AA therapy. Methods: Data from 409 consecutive patients treated in NI with radical EBRT (70-74 Gy/2Gy #) between 2005 and 2009 were reviewed. Baseline and treatment characteristics analysed comprised age at diagnosis, T stage, initial PSA (iPSA), Gleason score, age-adjusted Charlson comorbidity index (aCCI), ADT type and radiation dose. Outcomes included biochemical progression-free survival (bPFS; Phoenix), prostate cancer-specific survival (PCSS) and overall survival (OS). Cox Proportional Hazards model was used for multivariate analysis (MVA). Results: Men receiving LHRHa were significantly more likely to be older and have a higher iPSA. On MVA, factors independently associated with biochemical failure were T stage ≥ 3 and use of AA (p < 0.004 and p < 0.02 respectively). On MVA, the single independent factor for poorer OS was higher aCCI (p < 0.000015). There was a trend towards poorer OS in the LHRHa group (p = 0.087). Conclusions: An aCCI > 4 was the only independent factor for poorer OS. While there was a significantly increased rate of biochemical failure in the AA group, there was a trend towards poorer OS in the LHRHa group. This study suggests that AA may be a reasonable alternative to LHRHa therapy in men with localized PC treated with radical EBRT and ADT.