A systematic approach is presented to study the effect of a catalyst coating microstructure on its performance in a wall-coated steam methane reformer using response surface methodology. Three-dimensional simulation of diffusion and reaction are performed in several catalyst microstructures represented by packing of overlapping spheres. A surrogate model is developed based on Latin hypercube design of experiment and response surface methodology that relates the rate of hydrogen production in the catalyst coating microstructure to inter-particle porosity and average particle size. Two sets of simulations are done based on a kinetic model with two different sets of kinetic parameters and the results are compared. The comparison shows that the maximum rate of hydrogen production occurs at higher inter-particle porosity and smaller particle size, when the kinetics is faster and diffusion limitation is more severe. Copyright (C) 2015, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.