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Purpose We examined the impact of hypofractionated radiation therapy and androgen suppression therapy (AST) on quality of life (QOL) in high-risk prostate cancer patients. Methods Between March 2005 and March 2007, 60 patients with high-risk prostate cancer were enrolled in a prospective phase II study. All patients received 68 Gy (2.72 Gy per fraction) to the prostate gland and 45 Gy (1.8 Gy per fraction) to the pelvic lymph nodes in 25 fractions over 5 weeks. Of the 60 patients, 58 received AST. The University of California- Los Angeles Prostate Cancer Index questionnaire was used to prospectively measure QOL at baseline (month 0) and at 1, 6, 12, 18, 24, 30, and 36 months after radiation treatment. The generalized estimating equation approach was used to compare the QOL scores at 1, 6, 12, 18, 24, 30, and 36 months with those at baseline. Results We observed a significant decrease in QOL items related to bowel and sexual function. Several QOL items related to bowel function were significantly adversely affected at both 1 and 6 months, with improvement toward 6 months. Although decreased QOL scores persisted beyond the 6-month mark, they began to re-approach baseline at the 18- to 24-month mark. Most sexual function items were significantly adversely affected at both 1 and 6 months, but the effects were not considered to be a problem by most patients. A complete return to baseline was not observed for either bowel or sexual function. Urinary function items remained largely unaffected, with overall urinary function being the only item adversely affected at 6 months, but not at 1 month. Urinary function returned to baseline and remained unimpaired from 18 months onwards. Conclusions In our study population, who received hypofractionated radiation delivered using dynamic intensitymodulated radiotherapy with inclusion of the pelvic lymph nodes, and 2-3 years of AST prescription, QOL with respect to bowel and sexual function was significantly affected; QOL with respect to urinary function was largely unaffected. Our results are comparable to those in other published studies. [ABSTRACT FROM AUTHOR]