Membrane electrode assemblies (MEA) for polymer electrolyte membrane fuel cells (PEMFC) may possess as-manufactured non-uniformities in any of its constituent components. This article studies casting irregularities located within the PEM to understand their potential impact on MEA initial performance. Membrane material was cast on a lab-scale polymer casting line operating either within or at the boundaries of the process window. The resulting membrane material was either pristine in the former case, or, in the latter case, contained air bubbles, cracks, and other irregularities, ranging in size from about 0.6 to 3 mm. Spatial polarization experiments were conducted using a 121-channel segmented fuel cell system, and thermal imaging was performed subsequently to map hydrogen crossover to spatial performance. While total-cell polarization data was minimally impacted by the irregularities, the spatial diagnostics showed local performance impacts that, in operation over time, could cause degradation in performance or earlier failure of the MEA. Such impacts could lead to these irregularities being classified as defects, i.e., manufacturing variations that should be identified and not included in a fuel cell stack. Classification of irregularities as defects will ultimately assist the industry by contributing to the development of threshold detection limits for in-line quality control diagnostics.