Benefiting from the high selectivity of solid polymer membrane in transporting protons, proton exchange membrane water electrolyzer (PEMWE) have the unique capability of safely operating under asymmetric pressure between the cathode and anode (typically with the cathode under elevated pressure and the anode at ambient pressure). This capability is crucial for high-pressure hydrogen storage and transportation, as well as for rapid response to fluctuating renewable electricity. Although increased cathode pressure significantly simplifies system integration and reduce capital cost, the stability under asymmetric pressure operation has not been well studied and reported. In this work, durability tests under different pressure differences were carried out, and it was found that when the pressure difference between cathode and anode increases from zero to 3.0 MPa, the voltage decay rate increased over 15 times. The underlying reason is that the asymmetric pressure imposes additional mechanical stress on the anode catalyst layer from cathodic side, leading to increase of mass transfer resistance and irreversible structural damage, resulting in performance degradation. In view of this fact, the internal structure of the electrolyzer cell was optimized, and the uneven stress distribution and stress concentration was greatly reduced, thus mitigating performance degradation. This indicates that the stability of PEMWE is significantly affected by asymmetric pressure, additional measures need to be taken to address potential issues of catalyst layer structural damage arising from stress.