This paper presents an operation optimization method and demonstrates its application to a proton exchange membrane fuel cell system. A constrained optimization problem was formulated to maximize the efficiency of a fuel cell system by incorporating practical models derived from actual operations of the system. Empirical and semi-empirical models for most of the system components were developed based on artificial neural networks and semi-empirical equations. Prior to system optimizations, the developed models were validated by comparing simulation results with the measured ones. Moreover, sensitivity analyses were performed to elucidate the effects of major operating variables on the system efficiency under practical operating constraints. Then, the optimal operating conditions were sought at various system power loads. The optimization results revealed that the efficiency gaps between the worst and best operation conditions of the system could reach 1.2-5.5% depending on the power output range. To verify the optimization results, the optimal operating conditions were applied to the fuel cell system, and the measured results were compared with the expected optimal values. The discrepancies between the measured and expected values were found to be trivial, indicating that the proposed operation optimization method was quite successful for a substantial increase in the efficiency of the fuel cell system. (C) 2016 Elsevier Ltd. All rights reserved.