Background and ObjectiveIntensive psychotherapy assisted with 3,4-methylenedioxymethamphetamine (MDMA-AT) was shown in Phase 3 clinical trials to substantially reduce post-traumatic stress disorder (PTSD) symptoms compared to psychotherapy with placebo. This study estimates potential costs, health benefits, and net savings of expanding access to MDMA-AT to eligible US patients with chronic and severe PTSD.MethodsUsing a decision-analytic model, we compared the costs, deaths averted, and quality-adjusted life years (QALYs) gained of three, 10-year MDMA-AT coverage targets (25%, 50%, and 75%) compared to providing standard of care to the same number of eligible patients with chronic and severe PTSD. We used a payer perspective and discounted costs (in US$) and QALYs to 2020. We conducted one-way, scenario, and probabilistic sensitivity analyses and calculated the net monetary value of MDMA-AT using a cost-effectiveness threshold of $100,000 per QALY gained.ResultsExpanding access to MDMA-AT to 25–75% of eligible patients is projected to avert 43,618–106,932 deaths and gain 3.3–8.2 million QALYs. All three treatment targets are dominant or cost-saving compared to standard of care. Our sensitivity analyses found that accounting for parameter uncertainty and changes in various assumptions did not alter the main finding—MDMA-AT is dominant compared to standard of care.ConclusionExpanding access to MDMA-AT to patients with chronic and severe PTSD will provide substantial health and financial benefits. The precise magnitude is uncertain and will depend on the number of eligible patients and other inputs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-022-01122-0.