The present study aimed to investigate the human serum proteome wide interaction of titanium dioxide nanoparticles (TiO2-NPs). Methodologically, the specific interaction of serum proteins with TiO2-NPs were explored through high resolution proteomic profiling. Here we employed LC-MS/MS based HRMS protocol to explore the list of interacted proteins. Further, novel human serum proteins interacted with TiO2-NPs and its associated molecular pathways have been illustrated.