Using a variety of in situ techniques, we tracked the structural stability and concomitantly the electrocatalytic oxygen reduction reaction (ORR) of platinum nanoparticles on ruthenium-titanium mixed oxide (RTO) supports during electrochemical accelerated stress tests, mimicking fuel cell operating conditions. High-energy X-ray diffraction (HE-XRD) offered insights in the evolution of the morphology and structure of RTO-supported Pt nanoparticles during potential cycling. The changes of the atomic composition was tracked in situ using scanning flow cell measurements coupled to inductively coupled plasma mass spectroscopy (SFC-ICP-MS). We excluded Pt agglomeration, particle growth, dissolution or detachment as cause for the observed losses in catalytic ORR activity. Instead, we argue that Pt surface poisoning to be the most likely cause of the observed catalytic rate degradation. Data suggest that the gradual growth of a thin oxide layer on the Pt nanoparticles due to strong metal-support interaction is the most plausible reason for the suppressed catalytic activity. We discuss the implication of the identified catalyst degradation pathway, which appear to be specific for oxide supports. Our conclusions offer previously unaddressed aspects related to oxide-supported metal particle electrocatalyst frequently deployed in fuel cells, electrolyzers or metal air batteries.