Ethanol oxidation on platinum nanoparticles with well-characterized surfaces is studied using cyclic voltammetry and FTIR techniques. Their behavior is compared with that obtained for platinum single crystal electrodes, in order to rationalize their performance and to understand the effects of the surface structure and anion adsorption on the reactivity. The results clearly demonstrate that there are strong effects of anion adsorption and surface structure on the measured current and oxidation mechanism. Thus, the main product of ethanol oxidation on (111) preferentially oriented Pt nanoparticles is acetic acid, and the amount of CO2 produced can be considered negligible. On the other hand, (100) preferentially oriented Pt nanoparticles are effective for the cleavage of the C–C bond yielding adsorbed CO, which eventually is oxidized to CO2. This nanoparticles electrode has the highest catalytic activity at high potentials, whereas (111) preferentially oriented Pt nanoparticles are more active at low potentials. In addition, no significant differences in the activity are reported by using different supporting electrolytes, which indicates that adsorbed acetate, which results from the adsorption of acetic acid, hinders ethanol oxidation.