In this study, the effects of different non-uniform catalyst loading distributions that vary in both lateral and longitudinal directions on the performance of Polymer Electrolyte Membrane Fuel Cell (PEMFC) were numerically examined in detail. A two-phase, multi-component, transient and three-dimensional model was employed for simulating the performance of the cathode half-cell of the PEMFC. At the first step, the best longitudinal catalyst loading distribution was found. At the second step, several lateral distributions were superimposed to the noted longitudinal catalyst loading distribution and the performance of the PEMFC was evaluated for each distribution. Numerical results showed 3.1% enhancement for the longitudinal catalyst loading distributions; while 8% improvement was observed with a non-uniform catalyst loading distribution in both longitudinal and lateral directions. Results indicated that when lateral distribution is employed, liquid water saturation in the rib side is reduced. In the best longitudinal distribution, the ratio of platinum loading in longitudinal direction was 1.857 and the ratio of platinum catalyst from the center region of the catalyst layer to the rib side is varied in a wide range. In the case of the noted ratio more than 30, the enhancement in the PEMFC performance was insignificant. Finally, the effect of catalyst loading distribution was investigated on the polarization curves. It was found that the catalyst loading distribution is most effective at the high current densities while it has a minor effect at low current densities.