Oxide-supported precious metal nanoparticles are widely used industrial catalysts. Due to expense and rarity, developing synthetic protocols that reduce precious metal nanoparticle size and stabilize dispersed species is essential. Supported atomically dispersed, single precious metal atoms represent the most efficient metal utilization geometry, although debate regarding the catalytic activity of supported single precious atom species has arisen from difficulty in synthesizing homogeneous and stable single atom dispersions, and a lack of site-specific characterization approaches. We propose a catalyst architecture and characterization approach to overcome these limitations, by depositing ∼1 precious metal atom per support particle and characterizing structures by correlating scanning transmission electron microscopy imaging and CO probe molecule infrared spectroscopy. This is demonstrated for Pt supported on anatase TiO2. In these structures, isolated Pt atoms, Ptiso, remain stable through various conditions, and spectroscopic evidence suggests Ptiso species exist in homogeneous local environments. Comparing Ptiso to ∼1 nm preoxidized (Ptox) and prereduced (Ptmetal) Pt clusters on TiO2, we identify unique spectroscopic signatures of CO bound to each site and find CO adsorption energy is ordered: Ptiso ≪ Ptmetal < Ptox. Ptiso species exhibited a 2-fold greater turnover frequency for CO oxidation than 1 nm Ptmetal clusters but share an identical reaction mechanism. We propose the active catalytic sites are cationic interfacial Pt atoms bonded to TiO2 and that Ptiso exhibits optimal reactivity because every atom is exposed for catalysis and forms an interfacial site with TiO2. This approach should be generally useful for studying the behavior of supported precious metal atoms.