Earlier we reported that serum contains organ-specific opsonins which selectively enhance recognition of liposomes by macrophages in the specific organs of the reticuloendothelial system (Moghimi, S.M. and Patel, H.M. (1988) FEBS Lett. 233, 143-147). The results presented here describe the properties of these organ-specific opsonins which differentiate between liver-specific and spleen-specific opsonins responsible for the enhancement of phagocytosis of liposomes by Kupffer cells and spleen macrophage, respectively. Liver-specific opsonin is a heat-stable macromolecule which on heating or on freezing and thawing exhibits enhanced opsonic activity. Serum also contains a dialysable factor which inhibits its opsonic activity. On the other hand, the spleen-specific opsonin is a heat-labile macromolecule which is sensitive to freezing and thawing and requires a dialysable serum co-factor for its optimum opsonic activity on spleen macrophages. Removal of this factor from serum brings about an irreversible conformational change in the opsonin. Evidence suggests that the spleen-specific opsonin may be composed of more than one different opsonin molecule. It is suggested that the serum factor(s) that inhibits liver-specific opsonic activity and enhances the spleen-specific activity may not be the same molecule, but in both the cases the factor(s) may mediate its function by modifying the process of the opsonisation of liposomes or by influencing the interaction of the opsonised liposomes with the respective cells. We propose that purification of the organ-specific opsonins may provide an opportunity to target drug carriers selectively to a specific organ of the reticuloendothelial system, and help us to evaluate their role in the altered opsonin states known to exist in certain diseases.