Apolipoprotein (apo) A-I is the major protein constituent of plasma high density lipoproteins (HDL). HDL has been shown to promote cholesterol efflux from cells in vitro. Decreased plasma concentrations of HDL cholesterol and Apo A-I have been associated with premature coronary artery disease due to atherosclerosis in our society. A genetic HDL deficiency, familial hypoalphalipoproteinemia, appears to be fairly common in patients with premature coronary artery disease. The gene for Apo A-I has been isolated and characterized. Preliminary studies indicate that a specific Apo A-I gene polymorphism, detected following Pst I restriction enzyme digestion utilizing a specific probe, is significantly more common in subjects with premature coronary artery disease than in normal control subjects, and in some kindreds is associated with genetic HDL deficiency. This Apo A-I gene polymorphism is due to an alteration in the Apo A-I, Apo C-III intergenic region, near the 3' end of the coding region for Apo A-I. These observations have important implications for the detection of individuals genetically predisposed to premature coronary disease, as well as for providing insights into the mechanism leading to atherosclerosis.