Pt-transition-metal (PtM) alloy catalysts are widely used to catalyze oxygen reduction reaction (ORR) and CO oxidation. Here we report a systematic investigation of compositional, particle size, and catalytic activity changes of seven Pt0.5M0.5 having similar initial sizes and transition-metal content. We found that the extent of transition-metal dissolution from PtM nanoparticles increases when Pt is alloyed with more negative Vdissolve transition metals despite their strong alloy-formation energy, where Vdissolve or dissolution potential is the thermodynamic potential for transition-metal dissolution (M ⇔ Mn+ + n e −) at pH 0. Decreased transition-metal dissolution from PtM nanoparticles is accompanied by decreased positive shifts in the onset voltage of CO oxidation from surface-chemistrysensitive CO stripping after voltage cycling. Moreover, increasing the extent of transitionmetal dissolution and decreasing Vdissolve was correlated with the ORR activity of PtM nanoparticles. Our work suggests that the dissolution potential of the transition-metal solute in PtM alloying catalysts might be used to design catalysts with enhanced ORR activity and stability