Knowledge of degradation pathways of catalyst/support ensembles aids the development of rational strategies to improve their stability. Here, this is exemplified using indium tin oxide (ITO)-supported Platinum nanoparticles as electrocatalysts at fuel cell (FC) cathodes under degradation protocols to mimic operating conditions in two potential regimes. The evolution of crystal structure, composition, crystallite and particle size is tracked by in situ X-ray techniques (small and wide angle scattering), metal dissolution by in situ scanning flow cell coupled with mass spectrometry (SFC ICP-MS) and Pt surface morphology by advanced electron microscopy. In a regular FC operation regime, Pt poisoning rather than Pt particle growth, agglomeration, dissolution or detachment was found to be the likely origin of the observed degradation and ORR activity losses. In the start-up regime degradation is actually suppressed and only minor losses in catalytic activity are observed. The presented data thus highlight the excellent nanoparticle stabilization and corrosion resistance of the ITO support, yet point to a degradation pathway involving Pt surface modifications by deposition of sub-monolayers of support metal ions. The identified degradation pathway of the Pt/oxide catalyst/support couple contributes to our understanding of cathode electrocatalysts for polymer electrolyte fuel cells (PEFC).