Decreased high-density lipoprotein cholesterol (HDL-C) levels have been designated a major risk factor for cardiovascular disease, and there is considerable interest in identifying individuals with these abnormalities for appropriate management. Although low HDL-C may result from genetic factors, it is estimated that approximately 50% of cases may be secondary to other abnormal or disease states or to their treatment. Very low HDL-C levels, arbitrarily defined as <20 mg/dL, are uncommon, and are best known to result from major genetic mutations of key steps in HDL metabolism. Less well-described are secondary forms of severe HDL-C deficiency, which need to be distinguished from the primary causes. In this review, causes of severe acquired HDL-C deficiency are identified from the literature and are reviewed extensively. These include moderate to severe hypertriglyceridemia, critical illness, androgenic anabolic steroids, and acquired lecithin cholesteryl acyl transferase deficiency and liver disease. A relatively new entity referred to as the "disappearing HDL syndrome" was coined to describe the fairly rapid development of severe HDL-C deficiency in ambulant subjects with previously normal HDL-C and triglyceride levels. This may occur with peroxisome proliferation-activated receptor agonist treatment or in patients with benign or malignant paraproteinemias. Case discussions from our clinical experience are provided to illustrate to the practitioner the clinical context in which these severe acquired deficiencies of HDL occur.