Purpose We investigated whether pretreatment factors predicted time to prostate cancer-specific mortality (PCSM) after conventional-dose and conformal radiation therapy (CRT). Patients and Methods Between 1988 and 2002, 421 patients with low (prostate-specific antigen [PSA] level less than or equal to 10 ng/mL and biopsy Gleason score less than or equal to 6) or favorable intermediate-risk (PSA > 10 to 15 ng/mL or biopsy Gleason score 3 + 4, but not both factors) disease underwent CRT (median dose, 70.4 Gy). Cox regression multivariable analysis was performed to determine whether the PSA level, Gleason score, T category, or the percentage of positive cores (% PC) predicted time to PCSM after CRT. After a median follow-up of 4.5 years, 117 (28%) patients have died. Results The % PC was the only significant predictor (Cox P less than or equal to .03). The relative risk of PCSM after CRT for patients with greater than or equal to 50% as compared with less than 50% PC was 10.4 (95% CI, 1.2 to 87; Cox P = .03), 6.1 (95% CI, 1.3 to 28.6; Cox P = .02), and 12.5 (95% CI, 1.5 to 107; Cox P = .02) in men with a PSA less than or equal to 10 and Gleason score less than or equal to 6, PSA less than or equal to 10 and Gleason score less than or equal to 7, and PSA less than or equal to 15 and Gleason score :! 6, respectively. By 5 years after CRT, 5% to 9% compared with less than 1 % (log-rank P less than or equal to .01) of these patients experienced PCSM if they had greater than or equal to 50% compared with less than 50% PC, respectively. Conclusion CRT dose-escalation techniques, the addition of hormonal therapy, or both should be considered in the management of patients with low or favorable intermediate-risk disease and greater than or equal to 50% PC. (C) 2004 by American Society of Clinical Oncology.