The adsorption chemistry of CO on clean and Pt-supported TiO2 (110) was investigated. It was found that surface structure of TiO2 plays an important role in the chemistry that takes place at the surface. On the reduced (1 x 2)-reconstructed surface, CO desorbed at 140 and 170 K, while only desorption at 140 K was observed on the stoichiometric (1 x 1) surface. Additionally, CO dissociation, possibly due to the reduction by Ti3+, was observed on the Pt-supported (1 x 2) surface. On the Pt-covered surfaces, the chemistry of CO adsorption and desorption strongly depends on the size of Pt nanoclusters. With a decrease in cluster size, CO was found to desorb at higher temperatures. This unusual desorption chemistry is likely related to quantum size effects of Pt nanoclusters. Scanning tunneling spectra revealed that clusters below 20 Angstrom in diameter exhibited nonmetallic behavior, while those above 40 Angstrom were metallic. This transition of the properties of Pt nanoclusters from metallic to nonmetallic as the cluster size decreases correlates with stronger interaction of CO with Pt observed in temperature-programmed desorption spectra.