Lifetime limitations are still penalizing direct methanol fuel cell technology, otherwise outstandingly promising for sustainable portable power generation. Strong heterogeneous performance fading, related to uneven operating conditions, is known to be exacerbated in the upscaling process towards commercial applications, especially at local level. This work applies a localized optimization strategy, previously developed on lab-scale samples, on a commercial 180 cm2 membrane electrode assembly, analysing both current and potential distribution by means of a custom macro-segmented fuel cell provided with array of reference electrodes. Analysis based on local polarization curves and impedance spectroscopy demonstrates that water distribution, leading to local dehydration as well flooded areas, drives uneven operation and fading. Consequently, platinum loading at cathode electrode has been redistributed, sensibly improving current density heterogeneity and stability (voltage decay rate decreased from 148 to 53.8 μV h−1) over a 600 h degradation tests. Then, residual fading identified at outlet regions has been investigated by means of local electrodes potential analysis, demonstrating a highly uneven operation of both electrodes. This phenomenon is discussed as the evidence of localized hydrogen evolution, which is identified for the first time during nominal galvanostatic operation and suspected to contribute to uneven fading of components.