The metabolism of radiolabeled 125I-low density lipoprotein (LDL) was studied in cultured human aortic smooth muscle cells (SMC) to investigate potential mechanisms contributing to heart attack and stroke in young women taking oral contraceptive (OC) preparations. No consistent difference was discerned in the capacity of these cells to bind and internalize LDL following 24-hour exposure to pooled lipoprotein-poor (d greater than 1.25 gm/ml) serum from nonsmoking OC users and controls. However, significantly (p greater than 0.01) less soluble radioactive material was released into the media from dishes containing SMC incubated with OC serum, indicating that their capacity to degrade LDL was impaired. Increased amounts of both cholesterol and cholesterol ester and electron microscopic evidence of lipid accumulation were found in SMC grown for 12 days under standard culture conditions with 10% OC serum. This combination of in vitro findings suggests that OC use may accelerate the development of cardiovascular disease in some women by modifying the metabolism of LDL by cells of the arterial wall.