High-density lipoprotein (HDL) particles are made up of two major populations of particles, differing in composition and metabolism. Both contain apolipoprotein (apo) A-I but only one contains apo A-II. Lipoprotein particles that contain only apo A-I (LpA-I particles) can increase cellular cholesterol efflux from cultured cells in vitro. LpA-I:A-II particles, however, do not increase cholesterol efflux. LpA-I:A-II can be determined directly with an enzyme-linked differential antibody immunosorbent assay. LpA-I is determined by differential electroimmunoassay: in the presence of a large excess of anti-apo A-II, LpA-I:A-II particles are retained in one peak, whereas LpA-I migrates grates as a second peak. Both lipoprotein forms of apo A-I-containing particles are present mainly in HDL, but the relative proportion of LpA-I is greater in HDL2 than in HDL3. Concentrations of LpA-I in plasma samples from normolipemic subjects average approximately 10% higher in women than in men. The lower apo A-I concentrations in patients with significant coronary artery disease reflect a decrease in the LpA-I particles. Data obtained in octogenarians also support the possibility that LpA-I might represent the anti-atherogenic fraction of HDL. Moreover, the concentration of LpA-I in children of parents with premature coronary heart disease was lower than that of a control group without any family history of this disease. Nutrients and hypolipidemic drugs seem to affect the two kinds of particles differently.