The purpose of the present study was to investigate the effects of niceritrol on HDL metabolism. In study (A), niceritrol, 750 mg/day was given for initial period of 12 weeks and 1,500 mg/day was prescribed for an additional 12 weeks to 12 subjects. In six of them, the HDL cholesterol (Ch) levels were less than 45 mg/100 ml with normal plasma cholesterol levels and with plasma triglyceride levels of less than 250 mg/100 ml. In the remaining six subjects, HDL-Ch, plasma cholesterol and triglyceride levels were all within normal limits except in one subject having a higher triglyceride level, 213 mg/100 ml. Plasma lipoproteins were fractionated by sequential ultracentrifugation and analyzed for cholesterol, triglyceride (TG), phospholipid(PL), apolipoprotein(Apo) B and Apo A-I, every 4 weeks. Niceritrol decreased plasma-Ch, VLDL-Ch, LDL-Ch, plasma-TG, VLDL-TG, plasma-PL, VLDL-PL and LDL-PL. Niceritrol increased HDL-Ch and the HDL-Ch/LDL-Ch ratio. These effects were more significant for the dose of 1,500 mg/day than 750 mg/day and were more marked in the patients with lower pretreatment HDL-Ch levels. Apo B level at 20 weeks was significantly lower than that before treatment. Initial plasma Apo A-I levels of the patients were approximately one-half of the control plasma. After treatment with niceritrol, Apo A-I concentration tended to increase. In study (B), changes of lipids concentration in HDL2 and HDL3 fraction were investigated in 5 patients during treatment with niceritrol, 1,500 mg/day for 8 weeks. Lipoproteins were analyzed every 2 weeks. HDL2-Ch levels tended to increase without significant changes of HDL3-Ch levels and HDL2-Ch/HDL3-Ch ratio showed a tendency to increase. A significantly but weakly inverse correlation between changes of VLDL-TG and HDL-Ch was observed, suggesting that the increment of HDL might be due partly to promoted lipolysis of TG-rich lipoproteins. However, it was suggested that the effects of niceritrol on lipoprotein synthesis in the liver and HDL catabolism should be considered.