The effects of zymosan on lipid metabolism in mouse peritoneal macrophages (MPM) in vitro and in vivo were studied with special reference to the following parameters: i) 14C-oleate incorporation into cholesteryl esters (CE), triglycerides (TG), and phospholipids (PL) in MPM incubated with low density lipoproteins (LDL) and acetylated LDL; ii) cholesteryl-14C-oleate-acetyl LDL uptake and 125I-acetyl LDL degradation; iii) oxidative modification of LDL. Zymosan administered to mice caused significant stimulation of 14C-oleate incorporation into CE, TG, and PL with no effect on 3H-cholesterol (Ch) incorporation into CE or 3H-glycerol incorporation into TG and PL in MPM. The 14C-oleate incorporation into cellular lipids was unaffected by 18-hour incubation of MPM with zymosan (100-500 micrograms/ml) but increased after incubation of unstimulated MPM with blood serum and peritoneal fluid harvested harvested from zymosan-treated mice. One possible explanation of this phenomenon is oleyl-CoA formation induction in cytokine-stimulated MPM in vivo. Zymosan decreased the Ch-14C-oleate-acetyl LDL uptake, 125I-acetyl LDL degradation, and Ch esterification in the presence of acetyl LDL in MPM both in vitro and in vivo. An increase in Ch esterification after incubation of MPM with zymosan for 6-18 hours in the presence of LDL was accompanied by an increase in lipid peroxidation of LDL and its electrophoretic mobility. The data obtained suggest that the macrophage acetyl LDL receptor pathway may be inhibited by zymosan and that cytokines released from zymosan-stimulated cells may influence the generation of foam cells.