A surface structural preference for (1 0 0) terraces of fcc metals is displayed by many bond-breaking or bond-making reactions in electrocatalysis. Here, this phenomenon is explored in the electrochemical oxidation of dimethyl ether (DME) on platinum. The elementary C–O bond-breaking step is identified and clarified by combining information obtained from single-crystal experiments and density functional theory (DFT) calculations. Experiments on Pt(1 0 0), Pt(5 1 0), and Pt(10 1 0) surfaces show that the surface structure sensitivity is due to the bond-breaking step, which is unfavorable on step sites. DFT calculations suggest that the precursor for the bond-breaking step is a CHOC adsorbate that preferentially adsorbs on a square ensemble of four neighboring atoms on Pt(1 0 0) terraces, named as “the active site”. Step sites fail to strongly adsorb CHOC and are, therefore, ineffective in breaking C–O bonds, resulting in a decrease in activity on surfaces with increasing step density. Our combined experimental and computational results allow the formulation of a new mechanism for the electro-oxidation of DME as well as a simple general formula for the activity of different surfaces toward electrocatalytic reactions that prefer (1 0 0) terrace active sites.