The role of Salmonella typhimurium endotoxin in producing hypertriglyceridemia was investigated in 70 male rhesus monkeys. Dose-response studies were performed with 0.3-9.0 mg of endotoxin/kg injected intravenously; free fatty acids and triglycerides were measured during the subsequent 8 hr. The effect of endotoxin on lipid disposal mechanisms was assessed by both intravenous lipid-loading tests and total plasma lipolytic activity after administration of heparin. The possible interference of endotoxin with lipid-clearing enzymes was also explored. Smaller doses of endotoxin (0.3 and 0.9 mg/kg) produced significant increments in free fatty acids within 2-5 hr of administration, with minimal trilgyceride increments. Larger doses of endotoxin (2.8-9.0 mg/kg) failed to produce significant elevations in free fatty acids but did result in significant triglyceride increases 2-6 hr after administration. Within 4 hr after administration of 7 mg of endotoxin/kg, both tests showed impaired disposal of lipids. However, once lipid-clearing enzymes were activated, endotoxin did not reduce lipolytic activity in vitro. These results support the contention that endotoxin significantly elevates serum triglyceride concentrations and leads to impaired lipid disposal mechanisms by interfering with the activation of lipid-clearing enzymes.