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PURPOSE To compare the tumor control and toxicity in men with intermediate-risk prostate cancer treated with either external beam radiation therapy (EBRT) or EBRT plus low-dose-rate brachytherapy (combo-RT). METHODS AND MATERIALS Between 1995 and 2012, 579 men with intermediate-risk prostate cancer were treated with either EBRT (n = 388) or combo-RT (n = 191). Outcomes assessed included biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and cumulative incidence of genitourinary (GU) and gastrointestinal toxicity. Favorable and unfavorable intermediate-risk subgroups were analyzed. RESULTS Median followup was 7.5 years. Combo-RT group had improved 10-year bRFS compared with EBRT (91.7% vs. 75.4%, p = 0.014). On multivariable analysis, combo-RT (hazard ratio, 0.48; 95% confidence interval: 0.25, 0.92; p = 0.03) was associated with improved bRFS. Combo-RT had significantly improved bRFS compared with EBRT in the unfavorable subgroup (p = 0.02) but not in the favorable subgroup (p = 0.37). DMFS was similar within the entire cohort and by risk group. Combo-RT was associated with an increased rate in the 6-year cumulative incidence of Grade 3 GU toxicity (hazard ratio, 3.48; 95% confidence interval: 1.1, 11.1; p = 0.026); however, 57% of Grade 3 GU toxicity was resolved, 29% had partial improvement, and only 1 patient had persistent Grade 3 GU toxicity. CONCLUSIONS In intermediate-risk prostate cancer, combo-RT improved bRFS but not DMFS and increased Grade 3 GU toxicity. The bRFS benefit was limited to unfavorable intermediate-risk patients.