New lipid derivatives of polyethyleneglycol (PEG) have been synthesized and tested for the ability to allow liposomes to evade uptake by the reticuloendothelial system (RES) and to prolong the circulation time of liposomes in mice. Liposomes were prepared from distearoylphosphatidylcholine (DSPC) and cholesterol (CH) (1:1, m/m) containing 6 mol% of various PEG-derivatives. The activity of the CH derivative of PEG (CH-PEG) in prolonging the circulation time of liposomes was proportional to the average molecular weight of PEG, i.e., 4800 > 2600 > 1700 > 800. alpha-Methoxy-omega-(1,2-dioctadecenoyloxy glyceryl)polyoxyethylene (DO-PEG) 1000 and alpha-methoxy-omega-(1,2-ditetradecenoyloxy glyceryl) polyoxyethylene (DT-PEG) 1000, in which PEG is directly linked to glycerol, prolonged the circulation time as effectively as distearoylphosphatidyl-N-(methoxy polyoxyethylene succinyl)-ethanolamine (DSPE-PEG). PEG-derivatives with a functional group at the PEG terminal, such as distearoyl-phosphatidyl-N-(3-carboxypropionyl polyoxyethylene succinyl)ethanolamine (DSPE-PEG-COOH) and alpha-(dipalmitoylphosphatidyl)-omega-hydroxypolyoxyethylene (DPP-PEG-OH), effectively prolonged the circulation time of liposomes. Incorporation of PEG-derivatives did not change membrane fluidity even after treatment with serum. Furthermore, incorporation of PEG-derivatives into liposomes decreased uptake by J774 cells, a murine macrophage-like cell line, in vitro. The newly synthesized PEG-derivatives seem to prevent or reduce the interactions of liposomes with serum protein and macrophages, resulting in enhanced stability and a prolonged circulation time.