BACKGROUND: Randomized trials supported the use of androgen deprivation therapy (ADT) with radiation therapy (RT) for intermediate-risk prostate cancer. However, the value of concurrent ADT was less certain with dose-escalated RT. Better methods of stratifying patients in this risk group may help select patients who are most likely to benefit. METHODS: A total of 238 men with intermediate-risk (prostate specific antigen [PSA] 10-20, Gleason 7, or stage T2b-c) adenocarcinoma of the prostate were treated with external beam RT between 1989 and 2006. Patients had Gleason <= 6 (39%) or 7 (61%) tumors; median PSA was 10.5 ng/mL. A median of 37.5% of biopsy cores were positive from a median of 9 biopsy cores sampled. The median RT dose was 74 Gy to the prostate. A total of 112 patients (47%) received neoadjuvant and concurrent ADT (median, 4 months). Median follow-up period was 49 months. RESULTS: The freedom from biochemical failure (FFBF, nadir + 2 definition) was 93% at 3 years, 86% at 4 years, and 80% at 5 years. On univariate analysis, the only factor associated with FFBF was percentage of positive cores (PPC, P = .0340). The prognostic value of PPC >= 50 was not evident in patients receiving ADT (FFBF at 4 years 90% vs 91%, P = .3015). For patients not receiving ADT, the impact of PPC >= 50 (FFBF at 4 years 76% vs 93%, P = .0844) was more pronounced. On multivariate analysis, PPC (P = .0388) was significantly associated with FFBF, whereas Gleason sum, ADT, RT dose, PSA, and T-stage were not. CONCLUSIONS: After dose-escalated external beam RT, intermediate-risk prostate cancer patients with PPC >= 50 had the highest risk for biochemical failure and may be most likely to derive a benefit from ADT. Cancer 2009;115:1784-90. (C) 2009 American Cancer Society.