The incorporation of ganglioside GM1 or phosphatidylethanolamine-polyethyleneglycol conjugates into liposomes can result in extended circulation lifetimes in vivo. This has been attributed to an ability to avoid uptake by the reticuloendothelial system (RES), specifically the phagocytic cells of the liver and spleen. Here we examine whether a representative large unilamellar vesicle (LUV) formulation which contains GM1 (distearoylphosphatidylcholine/cholesterol/GM1, 45:45:10 mol/mol), actually does avoid the RES. It is shown that a pre-dose of LUVs which contain GM1 and entrapped doxorubicin blocks the accumulation of subsequently injected empty distearoylphosphatidylcholine/cholesterol liposomes in liver. It is therefore concluded that liposomes exhibiting extended circulation lifetimes can induce RES blockade and do not avoid uptake by liver phagocytes.