A comprehensive mathematical model for the cathode catalyst layer (CL) of a proton exchange membrane fuel cell (PEMFC) is developed to investigate its performance, which is determined by activation overpotential. Numerous cathode CL parameters such as the saturation and eight structural parameters, namely, ionomer film thickness covering each agglomerate, agglomerate radius, platinum loading, carbon loading, ionomer volume fraction, gas diffusion layer penetration content and its porosity, and CL thickness are taken into account. The main effects of each parameter and their interactions are investigated using the analysis of means (ANOM) and interaction plots, respectively. Analysis of variance (ANOVA) is used to identify the influence of the CL structural parameters on the activation overpotential. Finally, an evolutionary optimization algorithm is employed to maximize the cathode CL's performance. (C) 2011 Elsevier Ltd. All rights reserved.