The strong metal-support interaction (SMSI) is one of the most important concepts in heterogeneous catalysis. Herein we report a study of Pt-TiO2 SMSI using Pt/rutile TiO2(110) model catalysts with different Pt particle sizes by means of X-ray photoelectron spectroscopy, ion scattering spectroscopy, and the adsorption of probe molecules. The acquired results unambiguously demonstrate a size dependence of the Pt-TiO2 SMSI, in which SMSI occurs barely between supported Pt clusters and the TiO2(110) substrate but obviously between supported Pt nanoparticles and the TiO2(110) substrate. Such a size-dependent SMSI could be associated with size-dependent electronic structures of the supported Pt particles. These results highlight the sensitivity of the SMSI to the size of supported metal particles, which greatly advances the fundamental understanding.