A combined chemical/mechanical accelerated stress test (AST) was developed for proton exchange membrane (PEM) fuel cells based on relative humidity cycling (RHC) between dry and saturated gases at open circuit voltage (OCV). Membrane degradation and failure were investigated using scanning electron microscopy and small- and wide-angle X-ray scattering. Changes to membrane thickness, hydrophilic domain spacing, and crystallinity were observed to be most similar between field-operated cells and OCV RHC ASTs, where local thinning and divot-type defects are the primary failure modes. While RHC in air also reproduces these failure modes, it is not aggressive enough to differentiate between different membrane types in >1,333 hours (55 days) of testing. Conversely, steady-state OCV tests result in significant ionomer morphology changes and global thinning, which do not replicate field degradation and failure modes. It is inferred that during the OCV RHC AST, the decay of the membrane’s mechanical properties is accelerated such that materials can be evaluated in hundreds, instead of thousands, of hours, while replicating the degradation and failure modes of field operation; associated AST protocols are recommended as OCV RHC at 90◦C for 500 hours with wet/dry cycle durations of 30s/45s and 2m/2m for automotive and bus operation, respectively.