Optimization of operating conditions to obtain maximum power in PEMFCs could have a significant role to reduce the costs of this emerging technology. In the present experimental study, a single serpentine PEMFC is used to investigate the effects of operating conditions on the electrical power production of the cell. Four significant parameters including cathode stoichiometry, anode stoichiometry, gases inlet temperature, and cathode relative humidity are studied using Design of Experiment (DOE) to obtain an optimal power. Central composite second order Response Surface Methodology (RSM) is used to model the relationship between goal function (power) and considered input parameters (operating conditions). Using this statistical-mathematical method leads to obtain a second-order equation for the cell power. This model considers interactions and quadratic effects of different operating conditions and predicts the maximum or minimum power production over the entire working range of the parameters. In this range, high stoichiometry of cathode and low stoichiometry of anode results in the minimum cell power and contrary the medium range of fuel and oxidant stoichiometry leads to the maximum power. Results show that there is an optimum value for the anode stoichiometry, cathode stoichiometry and relative humidity to reach the best performance. The predictions of the model are evaluated by experimental tests and they are in a good agreement for different ranges of the parameters. (C) 2015 Elsevier Ltd. All rights reserved.