146 Background: High-risk localized prostate cancer (PC) has suboptimal treatment outcomes due to therapeutic resistance to radiation and hormone therapy. Previous studies suggest that anticoagulant (AC) use may improve treatment outcomes in high-risk PC. We hypothesized that AC therapy confers a freedom from biochemical failure (FFBF) and overall survival (OS) benefit in patients treated with concurrent radiotherapy in patients with high-risk prostate cancer defined as Gleason Score (GS) 8 or higher, Stage T3a or higher, or prostate-specific antigen (PSA) of 20 or more. Methods: Analysis was performed of 74 patients identified who were treated with definitive external beam radiotherapy with National Comprehensive Cancer Network defined high-risk PC from 2005 to 2008 at The University of Texas Southwestern Medical Center. Of these patients, 43 took concurrent AC including aspirin (95.6%), clopidogrel (17.8%), warfarin (20%), and multiple ACs (31.1%). Associations between AC use and FFBF, OS, distant metastasis, and toxicity were explored. A minimum of 5 years of follow-up were available for all patients. Results: For patients taking any AC compared to no AC, there was improved FFBF compared to of 84.4% versus 62.1% (P = 0.0003), and for aspirin the FFBF was 83.7% versus 64% (P = 0.0008). Aspirin was also associated with reduced rates of distant metastasis of 12.2% versus 26.7% in patients who did not take aspirin (P = 0.039). On multivariate analysis, patients taking aspirin with PSA of 20 or more had 5 year OS 95.8% versus 70% (P = 0.031), and GS 9-10 had 5 year OS 88.2% versus 37.5% (P = 0.013). Conclusions: AC use was associated with a FFBF benefit in high-risk PC which translated into an OS benefit in the highest risk PC patients with PSA of 20 or more or GS 9 to 10 who are most likely to experience prostate cancer specific mortality. This hypothesis generating data suggests AC use may represent an opportunity to improve patient outcomes by overcoming therapeutic resistance.