PURPOSE: This trial was designed to test the hypothesis that total androgen suppression and whole pelvic radiotherapy (WPRT) followed by a prostate boost improves progression-free survival (PFS) by > or =10% compared with total androgen suppression and prostate only RT (PORT). This trial was also designed to test the hypothesis that neoadjuvant hormonal therapy (NHT) followed by concurrent total androgen suppression and RT improves PFS compared with RT followed by adjuvant hormonal therapy (AHT) by > or =10%. METHODS AND MATERIALS: Patients eligible for the study included those with clinically localized adenocarcinoma of the prostate and an elevated prostate-specific antigen level of <100 ng/mL. Patients were stratified by T stage, prostate-specific antigen level, and Gleason score and were required to have an estimated risk of lymph node involvement of >15%. RESULTS: The difference in overall survival for the four arms was statistically significant (p = 0.027). However, no statistically significant differences were found in PFS or overall survival between NHT vs. AHT and WPRT compared with PORT. A trend towards a difference was found in PFS (p = 0.065) in favor of the WPRT + NHT arm compared with the PORT + NHT and WPRT + AHT arms. CONCLUSIONS: Unexpected interactions appear to exist between the timing of hormonal therapy and radiation field size for this patient population. Four Phase III trials have demonstrated better outcomes when NHT was combined with RT compared with RT alone. The Radiation Therapy Oncology Group 9413 trial results have demonstrated that when NHT is used in conjunction with RT, WPRT yields a better PFS than does PORT. It also showed that when NHT + WPRT results in better overall survival than does WPRT + short-term AHT. Additional studies are warranted to determine whether the failure to demonstrate an advantage for NHT + WPRT compared with PORT + AHT is chance or, more likely, reflects a previously unrecognized biologic phenomenon.