PURPOSE: To compare, using a cost-effectiveness analysis, the quality-adjusted life expectancy (QALE) and cost between the 2 treatment options for intermediate- to high-risk prostate cancer: (1) radiation (RT) with androgen deprivation therapy (ADT) or (2) radical prostatectomy (RP) followed by adjuvant RT for patients with risk factors. METHODS AND MATERIALS: Our Markov model allowed patients to transition between health states with yearly probabilities of developing cancer recurrence and/or toxicity. Probabilities were assigned according to favorable intermediate, unfavorable intermediate, or high-risk prostate cancer groups. The primary analysis examined outcomes for patients aged 65 years, whereas secondary analyses explored the effects of younger age, elevated baseline cardiovascular risk, and the use of salvage therapy. One-way and probabilistic sensitivity analyses were performed. RESULTS: Across all primary and secondary analyses, and using a wide-range of assumptions, RT + ADT was the preferred treatment strategy for men with intermediate- to high-risk prostate cancer. The QALE was higher after RT + ADT by 0.5 to 1.14 quality-adjusted life years, compared with RP. Radiation plus ADT was cost-effective in all situations, falling beneath a threshold of $100,000 per quality-adjusted life year. Among all risk groups, a greater proportion of patients undergoing RP experienced single or multiple treatment toxicities. CONCLUSIONS: Radiation plus ADT may result in improved QALE compared with RP for intermediate- to high-risk prostate cancer. Although biochemical failure is similar between treatment groups, there is a higher rate of developing multiple toxicities among patients treated with upfront RP.