An efficient and systematic approach for finding the optimal operating conditions of hydrogen polymer electrolyte fuel cells has been developed by combining an efficient optimization method and a validated multi-resolution fuel cell simulation tool. Four control parameters including cell temperature, cathode stoichiometry, cathode pressure and cathode relative humidity are used to build the optimization objective, which is defined as the maximum overall efficiency of the fuel cell system under ideal or realistic system assumptions. Through the design of experiment method, a set of sample simulations are first carried out using the fuel cell simulation tool. An analytic metamodel is then constructed using the radial basis function approach based on the simulation results. A feasible sequential quadratic programming scheme is then employed to optimize the metamodel to achieve the global optimal solutions. The study shows that different optimal solutions exist for different system assumptions, as well as different current loading levels, classified into small, medium and large current densities. The approach adopted in this study is generic and can be readily applied to more control parameters and further to the fuel cell design optimizations.