BACKGROUND: Discrepancies exist regarding the impact of neoadjuvant hormone therapy (NHT) on the risk of allcause mortality (ACM) in men who receive brachytherapy for localized prostate cancer. Therefore, the objective of the current study was to examine the effect of NHT on the risk of ACM in men with prostate cancer who receive with brachytherapy. METHODS: The study cohort included 2474 men with localized prostate cancer who either received NHT (N ¼ 1083) or did not receive NHT (N ¼ 1391) and brachytherapy without supplemental external beam radiation between 1991 and 2005 at centers within the 21st Century Oncology Consortium. All men had at least 2 years of follow-up. Low-risk, intermediate-risk, and high-risk disease was present in 65%, 23%, and 12% of men, respectively. A Cox regression multivariate analysis was used to evaluate the risk of ACM in men who received NHT compared with all others adjusting for age, prostate-specific antigen level, Gleason score, and tumor classification. RESULTS: After a median follow-up of 4.8 years (interquartile range, 3.3-7.5 years) and adjusting for known prostate cancer prognostic factors and age, treatment with NHT was associated significantly with an increased risk of ACM (adjusted hazard ratio, 1.24; 95% confidence interval, 1.01-1.53; P ¼ .04) in men aged 73 years. In men who were younger than the median age of 73 years, hormone therapy use was not significant (P ¼ .34). CONCLUSIONS: Compared with men who were younger than the median age of 73 years, men aged 73 years with localized prostate cancer who received brachytherapy and NHT had an increased risk of ACM compared with men who did not receive NHT. Cancer 2010;116:837-42.