In this article, we describe a 46-year-old man with severe high-density lipoprotein (HDL) deficiency and his kindred. In the proband, HDL cholesterol and apolipoprotein (apo) A-I levels were 5 and 4.5 mg/dL, respectively. Xanthomata, xanthelasma, arcus corneae, and hepatosplenomegaly were not present. The proband had coronary artery disease, but it was impossible to state whether the HDL deficiency cosegregated with premature coronary artery disease in this kindred. Pedigree analysis was suggestive of a codominant familial disease. Polymerase chain reaction amplification of the apoA-I gene of the proband, followed by subcloning and sequencing, did not reveal any mutation in either the coding regions or intron-exon junctions. A kinetic study using deuterated leucine to endogenously label apoA-I was performed to elucidate the metabolic basis of the apoA-I deficiency. We demonstrated marked hypercatabolism of apoA-I in the proband, with a fractional catabolic rate more than 10 times faster than normal; the plasma residence time of apoA-I in the proband was only 0.38 day compared with 4.10 days in a control subject. The apoA-I production rate was also substantially decreased in the proband. The association of a normal apoA-I gene sequence with marked hypercatabolism of apoA-I is similar to that described in Tangier disease. However, except for the presence of mild, diffuse, corneal deposits, this patient had no evidence of the reticuloendothelial cholesterol deposition characteristic of Tangier disease. This study establishes that a form of severe hypoalphalipoproteinemia distinct from Tangier disease can be caused by marked hypercatabolism of a normal A-I apolipoprotein.