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 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: Clinical data from 477 consecutive PC patients treated with radical EBRT (70-74 Gy) between 2005 and 2009 in Northern Ireland were reviewed. Detailed clinical information was obtained via an electronic medical record, a radiological results system and a pathological results database. Baseline and treatment characteristics analysed comprised age at diagnosis, clinical T stage, initial PSA, Gleason score, age-adjusted Charlson Comorbidity Index (aCCI), ADT type and EBRT dose. Outcomes of interest included biochemical progression-free survival (bPFS), prostate cancer-specific survival (PCSS) and overall survival (OS). Results: Complete data for 409 patients were available. At a median follow-up of 75 months, 5-year bPFS was 81%, PCSS was 98% and OS was 95% in the AA group and 92%, 98% and 88% respectively in the LHRHa group (p = 0.158 for the biochemical failure (BF) group and 0.25 for the OS group; insufficient events to assess PCSS). Men receiving LHRHa were significantly more likely to be older and have a higher iPSA. Conclusions: In this retrospective study, we found that an aCCI ≥ 4 was the only independent factor for poorer OS. While there was a significantly increased rate of BF in the AA group, there was a trend towards poorer OS in the LHRHa group. These data suggest that AA may be a reasonable alternative to LHRHa therapy in men with localized PC treated with radical EBRT and ADT.