The innate immune system is important for defense against foreign pathogens, such as bacteria and viruses. We hypothesized that the innate immune system is also important for the interaction between cells and nanomaterials, because cells do not have a specific defense system for nanomaterials. In this study, we demonstrated the effect of Toll-Like Receptor 4 (TLR 4), which is an important molecule for the innate immune system, on the uptake of TiO2 nanoparticles (NPs). The results indicated that TLR 4 expression vector-transfected cells increased the uptake of TiO2 NPs and also increased IL-6 mRNA induction by TiO2 NP exposure. Modifying TiO2 NPs with polyethylene glycol (PEG) reduced their uptake and inflammatory-signal transduction via TLR 4. Our results suggest that TLR 4 is important for interactions between cells and NPs, and that PEGylation of TiO2 NPs reduces the cellular response via interaction with TLR 4.