The binder effect was investigated on the interfacial stability and the cell performance of membrane electrode assembly (MEA), when Nafion® and sulfonated poly(ether ether ketone) (sPEEK) ionomers were used as binders. When sPEEK membrane was employed in the MEA fabrication, sPEEK ionomer illustrated better cell performance with lower electric-surface resistance than Nafion® ionomer under the 30% relative humidity (RH), whereas the outcome is vice versa at 100% RH. This different result was caused by the interfacial stability between the catalyst and membrane via binder as well as the proton conductivity of binder. Even though the proton conductivity of Nafion® ionomer was higher than that of sPEEK, the compatibility between sPEEK membrane and sPEEK ionomer was better than that between sPEEK membrane and Nafion® ionomer. At 30% RH, this interfacial stability, rather than proton conductivity of the ionomer, has more significant effect on the cell performance, as the SEM-morphology analysis showed that application of the Nafion® ionomer resulted in the delamination of the membrane from the catalyst layer. At the 100% RH, the proton conductivity of the binder was the main contribution to the cell performance, as an interfacial problem was not evident between the two layers.