We show that at the subnano scale, the catalytic properties of surface-supported clusters can be majorly impacted by strategic doping and the choice for the supporting surface. This is a first-principles investigation of CO oxidation catalyzed by two subnanoclusters, Pd4Au and Pd5, deposited on rutile TiO2(110) surfaces. The titania surface was found to participate in the reaction directly via providing additional reaction pathways. The bimetallic cluster Pd4Au shows enhanced catalytic activity, whereas the monometallic Pd5 is poisoned and deactivated in the presence of CO and oxygen, and this trend is reversed from that in the gas phase.