OBJECTIVES: Primary stroke centers (PSC) have been shown to improve survival in patients with acute ischemic stroke (AIS). The objective of this study was to evaluate the cost-effectiveness of treating AIS patients in a PSC compared with a non-PSC hospital setting. METHODS: A decision analytic model was developed to project the lifetime outcomes and costs for AIS patients. Clinical data were derived from a recent observational study comparing existing PSC- and non-PSC-admitted patients, the NINDS and ECASS III clinical trials, longitudinal cohort studies, and health state preference studies. Annual cost data were based on Medicare reimbursement and other published sources, and did not include start-up costs. The model used a health care payer perspective, and the primary outcomes were incremental life expectancy, quality-adjusted life years (QALYs), and health care costs. Sensitivity and scenario analyses were performed to evaluate uncertainty in the results. RESULTS: Admission to an existing PSC resulted in a gain of 0.22 years of life (95% credible range [CR], 0.12 - 0.33) and 0.15 QALYs (95% CR, 0.08 - 0.23) per patient, at a cost of $3600 (95% CR, $2400 - $5000) per patient, compared with admission to a non-PSC hospital. The incremental cost per QALY gained was $24,000, and the results in all probabilistic simulations were below the $100,000/QALY threshold. The cost-effectiveness improved as the number of stroke patients admitted per year and use of recombinant tissue plasminogen activator increased. CONCLUSIONS: Modeling analyses support the hypotheses that PSCs provide meaningful long-term benefits to AIS patients and are cost-effective.