Based on a multiscale modeling framework, we focus on understanding the impact of CO adsorption on the intrinsic stability properties of PtxCoy nanoparticles under PEMFC anode operating conditions. Firstly, CO adsorption effect on PtxCoy has been studied by using Monte Carlo (MC) simulation. Then, the MC results were coupled with a non-equilibrium thermodynamics kinetics model (MEMEPhys (R)) to simulate the effect of CO poisoning on the activity and durability of PtxCoy nanoparticles as HOR catalysts. The results are compared with simulations carried out on Pt, where potential self-oscillatory behaviour is observed and experimentally confirmed. The PtxCoy HOR activity and stability properties reveal to be strongly dependent on the nanoparticle size and composition. For certain nanoparticle sizes, simulations show that PtCo nanoparticles provide better CO tolerance than Pt3Co. However, the CO tolerance of PtCo degrades faster than that of Pt3Co in long-term operation. From both modeling and experimental approaches, it is demonstrated for the first time that this observation is due to the fact that CO adsorption enhances Cobalt dissolution. (C) 2011 The Electrochemical Society. [DOI: 10.1149/2.039111jes] All rights reserved.