Purpose To report the final results on treatment outcomes of a randomized trial comparing conventional and hypofractionated radiotherapy in high-risk, organ-confined prostate cancer (PCa). Patients and Methods This single-institution, randomized clinical trial, conducted from January 2003 to December 2007, enrolled 168 patients with high-risk PCa who were randomly assigned in a 1:1 ratio to conventional (80 Gy in 40 fractions in 8 weeks) or hypofractionated radiotherapy (62 Gy in 20 fractions in 5 weeks) to prostate and seminal vesicles. The primary outcome measure was late toxicity. Additional outcomes were freedom from biochemical failure (FFBF), prostate cancer-specific survival (PCaSS), and overall survival (OS), evaluated on an intention-to-treat basis. Results A total of 85 patients were assigned to conventional and 83 to hypofractionated radiotherapy. At a median follow-up of 9 years (interquartile range, 7.5 to 10.1 years), no differences was observed in physician-assessed late gastro intestinal and genitourinary toxicity greater than or equal to grade 2 ( P = .68 and .57, respectively) were found between the two arms. The 10-year FFBF rate was 72% in the hypofractionation group and 65% in the conventional fractionation group ( P = .148). Ten-year OS rates were 75% in the hypofractionation group and 64% in the conventional group, respectively ( P = .22). The same features for 10-year PCaSS were 95% and 88%, respectively ( P = .066). Hypofractionation, pretreatment prostate-specific antigen level, Gleason score, and clinical tumor stage for FFBF, and hypofractionation and Gleason score for PCaSS were significant prognostic variables on the multivariate analysis. Conclusion Long-term findings showed that hypofractionated radiotherapy failed the intent of either reducing physician-assessed late toxicity or maintaining the same efficacy. A postrandomization analysis, however, revealed that hypofractionation was a significant prognostic factor for FFBF and PCaSS, when adjusted for clinical prognostic variables.