The performance of the CO preferential oxidation (PROX) process was compared with the CO selective methanation (SMET) one, both applied as the last clean-up process step of a fuel processor unit (FPU) to remove CO from syngas. The FPU was completed with the reformer (autothermal reformer ATR or steam reformer SR) and a non-isothermal water gas shift (NI-WGS) reactor. Furthermore, the reforming of different hydrocarbon fuels, among those most commonly found in service stations (gasoline, light diesel oil and compressed natural gas) was examined. The comparison, in terms of different FPU configurations and fuels, was carried out by a series of steady-state system simulations in Aspen Plus®. From the obtained data, the performance of CO-PROX was not very different from that of CO-SMET, making it complex to give a definitive answer on the best FPU scheme. The most promising fuel processor with respect to performance is a chain of ATR, NI-WGS and CO-SMET. However, maintaining the same chain of clean-up reactors, the FPU with SR instead of ATR could also be a satisfactory choice. Even if there are lower efficiencies and H2 specific production compared to the ATR-based FPU, the SR-based one does not produce a syngas with the high N2 concentration typical of the ATR-based FPU. The syngas dilution by nitrogen is somehow detrimental for the stack efficiency, when syngas feeds PEM-FCs, since it lowers the polarization curve.