Recent studies with PEG liposomes in patients have consistently shown that liposomes can induce side effects (flushing, tightness of the chest). Furthermore, the blood clearance of PEG liposomes was shown to be dose-dependent: at lipid doses lower than 1 micromol/kg, PEG liposomes do not show the long-circulation property but instead are cleared relatively rapidly from the bloodstream. Another remarkable observation was that repeated injections of PEG liposomes led to significant pharmacokinetic changes: the circulatory half-life of a second dose of radiolabeled PEG liposomes dramatically decreased when given from 5 days to up to 4 weeks after a first injection. In these three unexpected phenomena, proteins of the complement system seem to play a key role. Therefore, one has to consider that PEG liposomes are not inert drug-carrying vehicles in vivo. Pharmacological effects can occur, induced solely by using liposomal particles irrespective of the drug content.