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Background: This paper deals with the location of emergency medical stations where ambulances waiting to be dispatched are parked. The literature reports a lot of mathematical programming models used to optimize station locations. Most studies evaluate the models only analytically applying the same simplifying assumptions that were used in the modelling phase. In addition, they concentrate on systems operating one type of emergency units in homogeneous urban areas. The goal of our study is to identify which optimization criterion the emergency medical service (EMS) outcomes benefit from the most and which model should be used to design tiered systems in large urban–rural areas. Methods: A bi-criteria mathematical programming model is proposed. The criteria include the accessibility of high-priority patients within a short time limit and average response time to all patients. This model is being compared to the p-median model with a single response time objective and to a hierarchical pq-median model that considers two different vehicle types. A detailed computer simulation model is used to evaluate the solutions. The methodology is verified in the conditions of the Slovak Republic using real historical data on 149,474 ambulance trips performed in 2015. Results: All mathematical models improve EMS performance by relocating some stations compared to the current distribution. The best results are achieved by the hierarchical median-type model. The average response time is reduced by 58 s, the number of calls responded to within 15 min is increased by 5% and the number of high-priority calls responded to within 8 min by 6%. Conclusions: The EMS systems operating in heterogeneous areas should be designed to minimize response times, and not to maximize the number of calls served within a given time limit. [ABSTRACT FROM AUTHOR]