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We earlier reported that PEGylated liposomes lose their long-circulating property when they are administered twice in the same animal within certain intervals. We recently proposed that anti-PEG IgM elicited by the first dose PEGylated liposomes selectively binds to the surface of a second dose, subsequently leading to substantial complement activation and complement-receptor mediated uptake of the second dose by hepatic Kupffer cells. In this study we found, by using a single-pass liver perfusion technique, that the first dose does not increase the intrinsic phagocytic activity of the Kupffer cells. It was also found that only serum obtained from rats that had received a first dose is able to enhance the hepatic uptake of test dose. The conditioned-serum-dependent hepatic uptake was completely abolished by pre-treatment of the serum at 56 °C for 30 min, which inhibits the complement activity. Conclusively, our results strongly support our earlier proposal that complement activation caused by anti-PEG IgM elicited by the first dose is a major cause of the initiation of the accelerated blood clearance of a subsequent dose PEGylated liposome in the ABC phenomenon.