Numerous epidemiologic studies demonstrated an inverse correlation betwcen plasma high density lipoprotein (HDL) cholesterol levels and the incidence o f coronary heart disease (CHD). Although a detailed mechanism for the antiathcrogenic effect of HDL has not been clarified yet, reverse cholesterol transport (RCT) is a possible major protective system against atherosclerosis. In this system, HDL removes cholesterol from atherosclerotic lesions. The removed cholesterol is finally cleared from the circulation by the liver, a terminal of RCT. HDL deficiency is often accompanied by premature CHD and corneal opacification, a sign of lipid accumulation in tissue. We previously reported two cases with a marked hyperalphalipoproteinemia (HALP) associated with low hepatic triglyceride lipase (HTGL) who suffered from CHD and juvenile corneal opacification (Atherosclerosis 53: 207-212, 1984). Therefore, we consider that HALP may not be a desirable condition and may be a disorder due to an impairment in each step of the RCT system. Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that functions to transfer cholesteryl ester (CE) from HDL to apolipoprotein (Apo) B containing lipoproteins. We recently identified CETP deficiency from an analysis of subjects with marked HALP. We reported that homozygous patients with CETP deficiency had qualitative and quantitative abnormalities of low density lipoproteins (LDL) as well as HDL, suggesting that CETP plays a crucial role in the modulation of both LDL and HDL particles. We also identified two different mutations in the CETP gene. One is a G-to-Amutation at the +1 position of intron 14 (IN 14), which causes an impairment of pre-mRNA splicing. The other is a missense mutation in exon 15 (D 442: G).