Carboxylated (4%) multi-walled carbon nanotubes were covalently functionalized with poly(ethylene glycol)(1000) (PEG(1000)), PEG(1500) and PEG(4000) with a PEG loading of approximately 11% in all cases. PEG loading generated non-uniform and heterogeneous higher surface structures and increased nanotube width considerably, but all PEGylated nanotube species activated the complement system in human serum equally. Increased PEG loading, through adsorption of methoxyPEG(2000(or 5000))-phospholipid conjugates, generated fewer complement activation products; however, complement activation was never completely eliminated. Our observations address the difficulty in making carbon nanotubes more compatible with innate immunity through covalent PEG functionalization as well as double PEGylation strategies. (C) 2013 Elsevier Inc. All rights reserved.