Lipid and lipoprotein concentrations, including high density lipoproteins (HDL) and its subfractions, were contrasted in subjects with Type IV hyperlipoproteinemia, before and after therapy with clofibrate. Very low density lipoprotein (VLDL) levels were raised, whereas both low density lipoprotein (LDL) and HDL values were reduced in the patient group. Clofibrate reversed this trend and VLDL cholesterol and protein levels fell to approximate control values. LDL and HDL cholesterol increased but remained significantly lower than in normal controls. However, LDL and HDL protein did approach control values. Of the HDL subfractions, HDL-3 was significantly reduced in the group with Type IV hyperlipoproteinemia. Clofibrate resulted in a significant increase in the HDL-2: HDL-3 cholesterol ratio, but had only a modest effect on HDL-3 concentrations. HDL-3 may be the critical HDL subfraction responsible for the inverse correlation between levels of HDL and the development of ischemic heart disease.