The effects of automotive-related lithium-ion module design, i.e. module stiffness and initial compression during module assembly on cell aging, swelling and pressure evolution are still largely unknown. This paper presents the results of a long-term aging study of 12 large-format automotive graphite/NMC 622 pouch cells, cycled for different module stiffnesses and initial compressions using design of experiments. Statistical analysis of mechanical and aging data revealed significant nonlinear (interaction) effects of both factors on pressure evolution, capacity loss and increase in internal resistance of the cells. Pressure dependent cell aging is observed over 1000 cycles, which was related to loss of active material at the cathode from differential voltage analysis. Post-mortem analysis confirmed a cathode active material loss via half- and full-cell measurements of harvested electrodes. Cross-section SEM micrographs revealed increasing NMC-particle cracking with higher pressure. Based on this, a fatigue-based aging model was developed to describe the capacity loss due to pressure dependent particle cracking. The presented approach enables both improved modeling of pressure dependent aging and lifetime optimized module design Display omitted •Cell swelling and aging under module stiffnesses and initial compressions•Significant effects of both factors on cell aging and pressure evolution•Pressure correlates with capacity fade due to loss of cathode active material•Active material loss confirmed by half-cell measurements and SEM cross-sections•Fatigue-based aging model of cathode particle cracking