Fluid flow manifold plays a significant role in the performance of a fuel cell stack because it affects the pressure drop, reactants distribution uniformity and flow losses, significantly. In this study, the flow distribution and the pressure drop in the gas channels including the inlet and outlet manifolds, with U- and Z-type arrangements, of a 10-cell PEM fuel cell stack are analyzed at anode and cathode sides and the effects of inlet reactant stoichiometry and manifold hydraulic diameter on the pressure drop are investigated. Furthermore, the effect of relative humidity of oxidants on the pressure drop of cathode are investigated. The results indicate that increase of the manifold hydraulic diameter leads to decrease of the pressure drop and a more uniform flow distribution at the cathode side when air is used as oxidant while utilization of humidified oxidant results in increase of pressure drop. It is demonstrated that for the inlet stoichiometry of 2 and U type manifold arrangement when the relative humidity increases from 25% to 75%, the pressure drop increases by 60.12% and 116.14% for oxygen and air, respectively. It is concluded that there is not a significant difference in pressure drop of U- and Z-type arrangements when oxygen is used as oxidant. When air is used as oxidant, the effect of manifold type arrangement is more significant than other cases, and increase of the stoichiometry ratio from 1.25 to 2.5 leads to increase of pressure drop by 527.3%.