BACKGROUND: Two evidence-based therapies exist for the treatment of high-risk prostate cancer (PCA): externalbeam radiotherapy (RT) with hormone therapy (H) (RT þ H) and radical prostatectomy (S) with adjuvant radiotherapy (S þ RT). Each of these strategies is associated with different rates of local control, distant metastasis (DM), and toxicity. By using decision analysis, the authors of this report compared the quality-adjusted life expectancy (QALE) between men with high-risk PCA who received RT þ H versus S þ RT versus a hypothetical trimodality therapy (S þ RT þ H). METHODS: The authors developed a Markov model to describe lifetime health states after treatment for high-risk PCA. Probabilities and utilities were extrapolated from the literature. Toxicities after radiotherapy were based on intensity-modulated radiotherapy series, and patients were exposed to risks of diabetes, cardiovascular disease, and fracture for 5 years after completing H. Deterministic and probabilistic sensitivity analyses were performed to model uncertainty in outcome rates, toxicities, and utilities. RESULTS: RT þ H resulted in a higher QALE compared with S þ RT over a wide range of assumptions, nearly always resulting in an increase of >1 quality-adjusted life year with outcomes highly sensitive to the risk of increased all-cause mortality from H. S þ RT þ H typically was superior to RT þ H, albeit by small margins (<0.5 quality-adjusted life year), with results sensitive to assumptions about toxicity and radiotherapy efficacy. CONCLUSIONS: For men with high-risk PCA, RT þ H was superior to S þ RT, and the result was sensitive to the risk of all-cause mortality from H. Moreover, trimodality therapy may offer local and distant control benefits that lead to optimal outcomes in a meaningful population of men. Cancer 2012;118:258-