The effect of mast cell stimulation on the uptake of low density lipoproteins (LDL) by macrophages was tested in vivo in the peritoneal cavity of the rat, a site known to contain both macrophages and mast cells. The concentration of LDL in the peritoneal cavity was raised by injecting [14C]sucrose-labeled LDL ([14C]sucrose-LDL). In the treated rats, in the absence of mast cell stimulation, the uptake of LDL by the peritoneal macrophages was low. But when the peritoneal mast cells were concomitantly stimulated by intraperitoneal administration of compound 48/80, an agent known to induce mast cell degranulation, the rate of uptake of labeled LDL by macrophages rose by 7-24-fold. The reason for this rise was that exocytosed mast cell granules bound LDL and carried it into macrophages when phagocytosed. Thus, cyclohexanedione treatment of LDL, or injection of avidin along with LDL, 2 measures known to inhibit binding of LDL to mast cell granules, totally prevented the mast cell-dependent uptake of LDL. Furthermore transmission electron microscopic studies with gold-labeled LDL disclosed phagocytosis of LDL-bearing granules by the peritoneal macrophages. This is the first demonstration of a natural proteoglycan being able to enhance the rate of LDL uptake by macrophages in vivo. These observations on the relation between stimulation of mast cells and uptake of LDL by macrophages in vivo may have relevance in other sites where mast cells and macrophages coexist, such as the arterial intima.