Probucol, a widely used lipid lowering drug, reduces both low- and high-density (LDL and HDL) lipoprotein levels and can induce a regression of tissue lipid deposits in both animals and man. The suggested mechanism(s) involve the prevention of LDL oxidative modifications and, possibly, an improvement in the reverse cholesteryl ester transport system. Probucol administration to 10 hypercholesterolaemic patients increased the activity of the cholesteryl ester transfer protein (CETP) by 50%. The rise of CETP activity was significantly related with the plasma steady-state drug levels (r = 0.51, P less than 0.005), thus suggesting that probucol may directly stimulate CEPT synthesis and/or release. Furthermore, CETP activity was inversely related with HDL-cholesterol levels, both in the whole series of 10 patients (r = -0.56, P less than 0.001) and, more so, in the single individuals (r between -0.77 and -0.97), thus suggesting that the reduction of plasma HDL-cholesterol levels is a direct consequence of CETP stimulation. These findings support the hypothesis that an improvement in the reverse cholesteryl ester transport is a major mechanism of probucol and that this may explain the drug induced plasma lipoprotein changes.