Structurally and functionally abnormal VLDL exist in hypertriglyceridemic humans. These large abnormal VLDL, in contrast to large normal VLDL, interact with cell surface receptors. One large VLDL particle carries far more total cholesterol than one LDL particle. Receptor-mediated uptake of abnormal VLDL is injurious to endothelial cells and converts macrophages into foam cells in vitro. These observations lead to the hypothesis that if similar phenomena occur in vivo, abnormal VLDL, which have prolonged residence times and increased opportunity to interact with arterial cells, are atherogenic by promoting endothelial injury and initiating foam cell formation. Since premature atherosclerosis is associated with some forms of hypertriglyceridemia and foam cells accumulate in certain hypertriglyceridemic subjects, similar events may indeed occur in vivo.