We report the effect of chemical modification of multi-walled carbon nanotubes (MWNTs) on their activation of the human serum complement system, as well as the adsorption of human plasma proteins on MWNTs. Four different types of chemically-modified MWNTs were tested for complement activation via the classical and alternative pathways using haemolytic assays. Human plasma protein binding was also tested using an affinity chromatography technique based on carbon nanotube-Sepharose matrix. Covalent functionalization of MWNTs greatly altered the level of activation of the complement system via the classical pathway. For example, MWNTs functionalised with epsilon-caprolactam or L-alanine showed respectively >90% and >75% reduction in classical pathway activation compared with unmodified MWNTs. These results demonstrate for the first time that these types of chemical modification are able to alter considerably the levels of specific complement proteins bound by pristine MWNTs (used as a control experiment). The reduced levels of complement activation via the classical pathway, that are likely to increase biocompatibility, were directly correlated with the amount of C1q protein bound to chemically modified carbon nanotubes. An inverse correlation was also observed between the amount of complement factor H bound to chemically modified MWNTs and the level of complement consumption via the alternative pathway. Binding of human plasma and serum proteins to pristine and modified MWNTs was highly selective. The chemical modifications studied generally increased nanotube dispersibility in aqueous media, but diminished protein adsorption.