A 2D(1D) multi-scale membrane electrode assembly mathematical model is proposed to study the effect of micro-scale transport losses due to catalyst aggregation in the cathode catalyst layer of a fuel cell. In order to develop an analytical expression for micro-scale transport losses, previous agglomerate models assumed an oxygen reduction reaction order of one and neglected any proton transport effects. In this article, a numerical micro-scale spherical ionomer-filled agglomerate model is integrated with a two-dimensional membrane electrode assembly model in order to develop a flexible framework to study different charge, mass, and kinetic transport models that cannot generally be analyzed with an analytical formulation. Results show that there is a significant interplay between scales and that changes in micro-scale agglomerate properties can significantly affect agglomerate effectiveness and current density distributions in the catalyst layer while not significantly affecting overall cell performance. Using the proposed framework, the effects of: a) proton conductivity inside agglomerates, b) a non-equilibrium oxygen dissolution boundary condition, and c) electrochemical models with different oxygen reaction orders, are studied. (C) 2014 The Electrochemical Society. All rights reserved.