The "accelerated blood clearance" (ABC) phenomenon describes a syndrome whereby the circulation time of a second dose of injected liposomes is substantially reduced, while the hepatic and splenic accumulations increase. To avoid this unexpected immune response, we have modified liposomes with cleavable PEG-lipid derivatives (PEG-CHEMS and PEG-CHMC). The ABC phenomenon was induced by repeated injection of conventional PEG-DSPE-liposomes in rat body and was accompanied by a greatly increased uptake in the liver. In contrast, only a slight ABC phenomenon was induced by repeated injection of PEG-CHMC-liposomes and was accompanied by increased uptake in the liver. Repeated injection of PEG-CHEMS-liposomes did not induce either an ABC phenomenon or an increase in liver accumulation. Repeated injection of the cleavable PEG-lipid modified vesicles (tris (hydroxymethyl) aminomethane salt of cholesteryl hemisuccinate(CHST)) showed similar results to those found with the cleavable PEG-lipid modified liposomes. These cleavable PEG-lipid derivatives could lessen or eliminate the ABC phenomenon produced by repeated injection of PEGylated liposomes or vesicles. Consequently, these two cleavable PEG-lipid derivatives may not only prolong the circulation time of nanoparticles, but may also represent a solution to the ABC phenomenon.