We investigated the opsonic effect of serum on the phagocytosis of cholesterol-poor and cholesterol-rich liposomes with freshly prepared rat bone marrow and peritoneal phagocytes in suspension. The presence of serum in incubation increased the uptake of cholesterol-rich but not cholesterol-poor liposomes in bone marrow cells, whereas serum enhances phagocytosis of both liposome preparations in peritoneal phagocytes. The opsonic activity of serum on the uptake of liposomes by both cell types is destroyed by heat, ammonium hydroxide, and zymosan treatments of serum, which suggests the involvement of complement in phagocytosis of liposomes. However, bone marrow cells and peritoneal macrophages responded differently when incubated with dialysed or EGTA-chelated serum. These treatments result in complete loss of the opsonic effect of serum on the uptake of liposome in bone marrow cells. Addition of serum dialysate or divalent cations to dialysed serum do not reinstall its lost opsonic activity. Thus these results shade doubt on possibility of involvement of complements in phagocytosis of liposomes by bone marrow cells. Dialysed or EGTA-treated serum also failed to promote liposome uptake by peritoneal macrophages but unlike in the case of bone marrow cells replacement of divalent cations to such sera reinstalls its opsonic activity and enhances phagocytosis of liposomes by peritoneal macrophages. These observations suggest the involvement of different serum components on liposome uptake by bone marrow cells and peritoneal macrophages, and emphasize the complexities associated with RES-mediated blood clearance of the intravenously injected liposomes. The properties of these opsonins are compared with those of 'liver-' and 'spleen-specific' opsonins responsible for phagocytosis of liposomes by Kupffer cells and spleen macrophages, respectively . It is suggested that these tissue specific opsonins are responsible for distribution of intravenously injected liposomes in various organs of the reticuloendothelial system.