Risk for coronary artery disease is directly related to plasma levels of total and low-density lipoprotein (LDL) cholesterol and inversely related to high-density lipoprotein (HDL) cholesterol concentrations. Weight gain in four of five patients with hypercholesterolemia given colestipol for 37 +/- 6 months was associated with a decrease in HDL cholesterol levels and an increase in LDL cholesterol/HDL cholesterol ratios. Weight loss (-7 +/- 2 kg) in these five and two other patients given colestipol increased plasma HDL cholesterol (17% +/- 6%) and lowered total cholesterol (-8% +/- 1%), LDL cholesterol (-13% +/- 2%), and total triglyceride (-20% +/- 4%) concentrations. However, in six patients given treatment by diet alone (no colestipol), comparable weight loss (-6 +/- 1 kg) did not alter plasma HDL cholesterol or total triglyceride concentrations, but reduced total cholesterol (-9% +/- 3%) and LDL cholesterol (-11% +/- 3%) levels. These results suggest that weight reduction increases plasma HDL cholesterol levels only in those patients with hypercholesterolemia given colestipol but not in those given treatment by diet alone. Nevertheless, the effects of weight loss on plasma total cholesterol and LDL cholesterol levels were comparable in the two groups of patients. This indicates that weight loss is an important adjunct in the treatment of moderately obese patients with hypercholesterolemia and may reduce their risk for coronary artery disease by improving their lipid profiles.