With the aim of developing of emulsion carrier systems for lipophilic drugs with the potential for prolonged circulation in the blood or hepatic targeting, the in vivo disposition of four model compounds, i.e., [H-3]prostaglandin E(1), [H-3]retinoic acid, [C-14]cholesterol, and [C-14]cholesteryl oleate with calculated log PCoct values of 2.15, 6.61, 9.46, and 18.3, respectively, injected with various emulsion formulations, were studied in mice. Small sized emulsions of about 100nm in diameters, with compositions of egg phosphatidylcholine (PC): soybean oil=1:1 (small PC emulsion) and PC: egg sphingomyelin (SM): soybean oil=0.7:0.3:1 (small SM emulsion), and a conventional emulsion with a diameter of about 250nm and a composition of PC: soybean oil=1:1 (large PC emulsion) were compared. Highly lipophilic [C-14]cholesteryl oleate, a marker of emulsion particles, indicated diverse in vivo behaviors; i.e., the small SM emulsion produced prolonged circulation in the blood, and the small PC emulsion followed this, while the large PC emulsion was rapidly uptaken by the liver. Thus, a reduction in size and coating with SM on the surface of oil droplets resulted in avoidance of the reticuloendothelial system (RES). Disposition profiles of other test compounds differed, depending on their lipophilicities: [C-14]cholesterol showed disposition patterns in all formulations similar to those of [C-14]cholesteryl oleate, but moderately lipophilic [H-3]prostaglandin E(1) and [H-3]retinoic acid showed common disposition profiles, regardless of emulsion types, suggesting their rapid release from the emulsion carriers. These results suggest that small SM emulsion and large PC emulsion can act respectively as long circulating and liver targeting carriers for highly lipophilic drugs with log PCoct larger than 9.