A major research goal of liposome pharmacology is the selective delivery of drugs to target cell populations while minimizing extraction by phagocytic macrophages and blood monocytes of the reticuloendothelial system. The liver is an ideal organ for studying targeting strategies using a variety of liposomes, inasmuch as its discontinuous capillaries have fenestrae through which liposomes less than 0.2 microns in diameter may escape into the extravascular space. In a previous kinetic study, we proposed that the hepatic uptake of small unilamellar vesicles (SUV) in mice was compatible with a model of uptake involving dual, parallel pathways. One is a saturable, phagocytic pathway of uptake mediated by Kupffer cells, the other is a nonsaturable, pinocytotic pathway of uptake mediated by parenchymal cells, favoring the latter pathway at high liposomal dose (Beaumier et al., 1983). In the present study, we demonstrated by the techniques of liver cells fractionation that the uptake of either the bovine brain sphingomyelin/cholesterol (2:1; mole/mole) SUV or distearoyl phosphatidylcholine/cholesterol (2:1; mole/mole) SUV by hepatic parenchymal cells was enhanced markedly by increasing the amount of injected dose of SUV. As high as 85 to 90% of the total liver dose can be attributed to the uptake of SUV by the hepatic parenchymal cells alone, when the injected dose reaches at or above 7.5 to 10 micrograms of lipid per g b.wt. The dose effect on the uptake of liposomes by hepatocytes appears to be a general phenomenon of neutral SUV. Our data suggested that blockade by dose permits a feasible approach to target SUV to hepatic parenchymal cells.