A novel mathematical model for an entire proton exchange membrane fuel cell (PEMFC) is developed with its focus placed on the modeling and assessment of thermodiffusion effects that have been neglected in previous studies. Instead of treating catalyst layers as interfaces of nil thickness, the model presented here features a finite thickness employed for catalyst layers, allowing for a more realistic description of electrochemical reaction kinetics arising in the operational PEMFC. To account for the membrane swelling effect, the membrane water balance is modeled by coupling the diffusion of water, the pressure variation, and the electro-osmotic drag.The complete model consisting of the equations of continuity, momentum, energy, species concentrations, and electric potentials in different regions of a PEMFC are numerically solved using the finite element method implemented into a commercial CFD (Comsol 3.4) code. Various flow and transport phenomena in an operational PEMFC are simulated using the newly developed model. The resulting numerical simulations demonstrate that the thermodiffusion has a noticeable impact on the mass transfer for the oxygen. It is also revealed through a systematic parametric study that, as the porosity of gas diffusion layers and catalyst layers increase, the current density of an operational PEMFC may increase. Also, it is found that a PEM fuel cell can perform better with reasonable high operating pressure and temperature, as well as a supply of fully humidified gaseous reactants.