To evaluate the late health-related quality of life (HRQOL) after radical perineal prostatectomy (RPP) and identify the predictors of outcome. We performed a cross-sectional study of 266 consecutive patients who underwent RPP for clinically localized prostate cancer between July 1998 and December 2000. Of the 236 patients successfully contacted, 187 (79.2%) returned a validated patient self-assessment questionnaire, the Expanded Prostate Cancer Index Composite, a mean of 42.1 months (range 29 to 64) months after surgery. The median HRQOL scores were calculated in four disease-specific domains: urinary, bowel, sexual, and hormonal. Preoperative baseline information from a separate group of 144 consecutive RPP candidates from January 2002 to May 2003 was used for comparison. Univariate and multivariate logistic regression analyses were used to identify predictors of more favorable long-term HRQOL outcomes. No statistically significant differences were found in any of the domain-specific summary scores between the study and reference groups, except in the sexual domain (median score 19.2 versus 56.4; P = 0.001). The number of medical comorbidities was a statistically significant predictor of HRQOL summary scores in all domains (P <0.05). In addition, the urinary summary score was statistically significantly associated with income (P = 0.03), sexual summary with the use of erectile aids (P = 0.003), bowel summary with secondary radiotherapy (P = 0.001) and income (P = 0.002), and hormonal summary with androgen ablation (P = 0.004). The results of this study have shown that the long-term HRQOL of RPP patients in the urinary, bowel, and hormonal domains is favorable. HRQOL outcomes depend on a spectrum of factors, including the presence of comorbid disease, socioeconomic status, and secondary cancer treatments. Future studies should seek to address the efficacy of preserving the sexual domain HRQOL in patients undergoing bilateral nerve-sparing RPP.