Background We quantify the impact of implementing a stroke system of care requiring transport of individuals believed to have stroke to a primary stroke center, in rural and urban settings, based on time from symptom recognition to treatment, probability of receiving treatment within 3 hours of stroke onset, and probability of overcrowding. We use Indiana as an example. Methods We used discrete-event simulation to estimate outcomes for 2 scenarios: stroke system of care with enabling technology (mobile stroke unit, stroke team expansion) and stroke system of care with no enabling technology, as compared with the status quo. We considered patient flow from symptom recognition to treatment. Patient locations and stroke events were generated for the 92 Indiana counties in Indiana, subdivided into 1009 locations. We considered time from emergency medical service (EMS) arrival at onset to treatment, probability of tissue plasminogen activator administered within 3 h of onset, and percentage of patients admitted beyond the occupancy level at the comprehensive stroke center. Results Results varied by urbanicity. Under no enabling technology, having a stroke system of care improved outcomes for individuals in urban and suburban settings. However, in rural settings, the implementation of stroke system of care guidelines decreased the average rate of treatment within 3 h of stroke onset and increased the EMS arrival to treatment times compared with sending the individual to the closest provider. Enabling technologies improved outcomes regardless of setting. Discussion Geographic disparities tend to increase the number of transfers, decrease the rate of treatment within 3 h of onset, and increase transit time. This could be overcome through federal and state initiatives to reduce quality gaps in stroke care in rural settings and promote care with dedicated stroke wards.