The aim of the present study was to study the synergistic hepatoprotective effect of silymarin with phospholipids when it is encaged in microspheres so as to passively target it to liver and to compare these silymarin formulations with silymarin solution. Various silymarin loaded lipid emulsions were formulated which include formulation A prepared with soyabean oil as an internal oily phase, soya lecithin as surfactant and tween 80 as cosurfactant; formulation B which was same as formulation A but was filtered through 0.45μ membrane filter and finally steam sterilized for intravenous administration; formulation C containing soyabean oil as an internal oily phase, soya lecithin as surfactant, tween 80 and propylene glycol as cosurfactant / cosolvent. These formulations were compared for their release profile with silymarin solution in propylene glycol, i.e. formulation D. In vivo evaluation was carried out using three models i.e. phenobarbitone induced sleep time in mice, biochemical estimation of SGOT and SGPT enzyme levels and histopathological examination of rat livers. Results revealed that there was significant reduction in sleep time in the mice treated with silymarin loaded lipid microspheres (both p.o. as well as i.v.) when compared with control and even with plain lipid microspheres and silymarin solution and significant reduction in enzyme levels in silymarin lipid microspheres treated group when compared with control, plain lipid microspheres as well as silymarin solution treated group. Histopathological studies also supported the results obtained from the other two models. A positive outcome of these studies gave an insight that if silymarin is coupled with phospholipid in such microparticulate delivery systems, hepatoprotective effect of drug molecules can be pronounced further by self targeting nature and synergistic action.