BACKGROUND: The combination of external-beam radiotherapy and brachytherapy is used commonly to treat men with prostate cancer. In this analysis, the authors examined the rate of biochemical recurrence (BR) and late grade > or =3 genitourinary (GU) and gastrointestinal (GI) toxicity after treatment with external-beam radiotherapy and brachytherapy in a multiinstitutional, cooperative group setting. METHODS: All eligible patients received external-beam radiotherapy (45 Gray [Gy] in 25 fractions) followed 2 to 6 weeks later by an interstitial implant using iodine-125 to deliver an additional 108 Gy. BR was defined in 2 ways: according to the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Definition (ACD) and according to the Phoenix definition (PD) (prostate-specific antigen nadir +2 ng/mL). The Radiation Therapy Oncology Group(RTOG)/European Organization for Research and Treatment of Cancer late radiation morbidity scoring system was used to grade all toxicity. RESULTS: One hundred thirty-eight patients were enrolled, and 130 were eligible for the current analysis. The median follow-up for surviving patients was 49 months (range, 20-60 months). The 48-month estimate of late grade > or =3 GU/GI toxicity was 15% (95% confidence interval [95% CI], 8-21%), and the 48-month estimate of BR was 19% (95% CI, 12-26%) and 14% (95% CI, 8-20%) according to the ACD and PD, respectively. CONCLUSIONS: The morbidity observed in this multiinstitutional, cooperative group study was slightly higher than that reported in recent RTOG studies using brachytherapy alone or high-dose external-beam radiotherapy. The BR rate observed in this report was similar to that observed with high-dose external-beam radiotherapy alone in similar patients.