BACKGROUND: Treatment with mechanical thrombectomy (MT) remains inaccessible for many patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) and under-utilization prevails across healthcare systems. Increasing the number of thrombectomy centers and ambulance helicopters may alleviate these issues. AIM: This study aims to determine the most effective combination of optimally located ambulance helicopters and thrombectomy centers for the economically constrained healthcare system. METHODS: This nation-wide, observational study analyses anonymized patient-level registry data stretching over a 6-year study period in Sweden. It combines optimization modeling with cost-effectiveness analysis to generate combinations of optimally located thrombectomy centers and ambulance helicopters to compare with the current eight locations of thrombectomy centers in Sweden and no ambulance helicopters. The analysis extends to evaluate the cost-effectiveness of increasing the number of thrombectomy centers and ambulance helicopters when the current eight locations remain fixed. RESULTS: The most cost-effective solution comprises 11 thrombectomy centers and 14 ambulance helicopters, corresponding to densities of 1.05 and 1.34 per one million inhabitants, respectively. It yields an estimated annual incremental net monetary benefit (INMB) close to €13.6 million. In the extended scenario analysis, the most cost-effective solution comprised nine thrombectomy centers and 13 ambulance helicopters, with an estimated annual INMB of €3.8 million. CONCLUSIONS: The most cost-effective combination of optimally located thrombectomy centers and ambulance helicopters brings about substantial health gains for patients with AIS due to LVO, compared with the current eight locations of thrombectomy centers in Sweden and ambulance helicopters.