In this study we compared the ability of phenytoin, a microsomal enzyme inducer, to raise plasma high-density lipoprotein (HDL) levels in normolipidemic subjects and patients with primary hypoalphalipoproteinemia. In healthy control subjects, phenytoin caused a dose-dependent increase of plasma HDL, HDL2, and HDL3 cholesterol levels, up to 40% to 50%. Minor changes were recorded in the plasma concentrations of apolipoprotein (apo) A-I and apo A-II; the plasma level of the cholesteryl ester transfer protein (CETP) decreased by 42%. In contrast, none of the patients with hypoalphalipoproteinemia had changes in plasma HDL, HDL2, or HDL3 cholesterol, apo A-I, apo A-II, or CETP levels. These findings indicate that microsomal enzyme inducers are unsuitable to increase plasma HDL levels in high-risk patients with primary hypoalphalipoproteinemia, and they disclose a new mechanism, that is, decreased CETP-mediated transfer of cholesterol out of HDL, for the HDL-raising effect of microsomal enzyme inducers in healthy individuals.