High-density lipoprotein cholesterol (HDL-C) values <40 mg/dL have been shown to be an independent risk factor for coronary heart disease (CHD). Rare genetic disorders associated with marked human HDL deficiency include apolipoprotein A-I (apoA-I) deficiency with undetectable plasma apoA-I, which can be due to defects within the APOA1 gene resulting in lack of apoA-I secretion. Such patients have marked HDL deficiency, normal levels of triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), and they can have xanthomas and premature CHD. ApoA-I variants with amino acid substitutions, especially in the region of amino acid residues 50–93 and 170–178, have been associated with amyloidosis. Patients with homozygous Tangier disease have defective cellular cholesterol efflux due to mutations in the adenosine-5′-triphosphate (ATP)-binding cassette transporter A1, detectable plasma apoA-I levels, and only pre-β1 HDL in their plasma. They have decreased LDL-C levels and can develop neuropathy and premature CHD. Patients with lecithin: cholesterol acyltransferase deficiency have both pre-β1 and α4 HDL present in their plasma and develop corneal opacities, anemia, proteinuria, and kidney failure. HDL deficiency has been associated with hypertriglyceridemia, obesity, insulin resistance, and diabetes. Common familial disorders associated with premature CHD and low HDL are: (1) dyslipidemia, seen in 15% of families, (2) combined hyperlipidemia, seen in 14% of families, and (3) hypoalphalipoproteinemia, seen in 4% of families. A common feature of all these disorders associated with premature CHD is a marked deficiency of very large α1 HDL. Niacin is currently the most optimal treatment strategy to raise HDL-C and normalize the HDL particle profile in these patients.