Low (LDL) and high (HDL) density lipoproteins stimulate prostacyclin (PGI₂) synthesis in cultured rabbit and human aortic smooth muscle cells. In this respect, the efficacy of HDL exceeded that of LDL, HDL₃ being the most effective. HDL₃ obtained from hypoalphacholesterolemic patients' serum had a lesser stimulative effect on PGI₂ synthesis as compared with HDL₃ of normolipidemic subjects. Partially purified apoprotein A-1 stimulates the metabolism of ¹⁴C-arachidonic acid accompanied with enhanced formation of prostaglandins, especially 6-keto-PGI_1α. Within a 24 h incubation in the fetal calf serum-free medium, prostaglandins I₂ and E₁ (1 × 10⁻⁷ m) reduce the intracellular cholesterol level in human aortic smooth muscle cells by 30%. Total HDL fraction as well as HDL₃ and HDL_2b applied in combination with prostaglandins have a synergistic effect resulting in a 50% fall in intracellular cholesterol. Hypothetically, the uptake of cholesterol by HDL may include the following stages: (1) HDL interacts with the cell and activates the intracellular PGI₂ synthesis probably via apo A-1 modulatory action on arachidonic acid metabolism; (2) newly synthesized PGI₂ activates cholesteryl ester hydrolase leading to the formation of free cholesterol; (3) HDL takes up free cholesterol.