Patients with high-risk prostate cancer (HRPC) have many treatment options: external beam radiotherapy (EBRT) with or without low-dose rate (LDR) or high-dose rate (HDR) brachytherapy boost, ultra-hypofractionated radiotherapy (UH), or radical prostatectomy (RP). No randomized evidence supports an overall survival (OS) benefit of one option relative to the others, so appropriate treatment must consider patient life expectancy, quality of life, and cost. We compare these treatments to determine the technique resulting in the optimal quality-adjusted life years (QALYs) and cost-effectiveness.A Markov model was developed to simulate treatment options and downstream events for HRPC. The primary endpoints were average accumulated costs and QALYs. The cost analysis considered all aspects of therapy, including treatments and side effects. Secondary endpoints included biochemical recurrence (BCR) and OS. Five treatment approaches were considered: moderately hypofractionated EBRT + 18 months androgen deprivation therapy (ADT), EBRT + LDR boost with 12 months ADT, EBRT + HDR boost with 12 months ADT, UH with 18 months ADT, and RP + salvage radiotherapy (SRT) after BCR. Treatment outcome and toxicity data were determined from the ASCENDE-RT, Hoskin et al. HDR, HYPO-RT-PC, and ProtecT trials. Efforts were made to specifically assess outcomes for HRPC patients. One-way sensitivity analyses were performed, including the rates of death from non-prostate cancer, ADT use, and SRT after RP.The base case was simulated for 15 years (Table 1). EBRT + brachytherapy boost (either HDR or LDR) was the most cost-effective treatment option with equivalent QALYs to RP and lower total costs. Over a 5-year timeframe, QALYs were comparable across all strategies, but UH had the lowest cost. At 10 years, RP and brachytherapy boost showed similar QALYs and cost. On sensitivity analysis, increasing rates of metastatic progression from BCR and decreased patient compliance with recommended ADT led to increasing cost-effectiveness of brachytherapy boost. High SRT rates (≥ 75%) after BCR following RP led to eventual ascendancy of RP over brachytherapy boost in both cost and QALYs. Without SRT, RP was the most expensive strategy with comparable outcomes to EBRT alone. No treatment strategy resulted in improved OS over the other treatments.Our analysis suggests that brachytherapy boost in patients with HRPC is the most cost-effective strategy over a 15-year horizon. Over shorter timeframes, UH is the most cost-effective treatment. Finally, high rates of SRT are vital to optimizing outcomes for patients after RP.