The chemical composition of the major classes of lipids were evaluated in the plasma and in various other tissues of a 68-year-old woman with a syringomyelia-like syndrome affecting cranial, cervical and brachial regions. No tonsillar abnormalities were apparent on visual examination of the oropharynx but the absence of alpha-lipoproteins on serum lipoprotein electrophoresis prompted the tentative diagnosis of Tangier disease. The diagnosis was confirmed by lipid, lipoprotein and apolipoprotein analyses of the plasma. The plasma cholesterol was low (93-113 mg/dl) and the triglyceride concentration normal (133-160 mg/dl). The very low density lipoproteins had normal chemical composition and morphology, but migrated with beta rather than pre-beta mobility on paper electrophoresis. Low density lipoproteins were deficient in cholesteryl esters and enriched in triglycerides; their electrophoretic mobility and morphology were normal. A small amount of high density lipoprotein (approximately 1.4 mg/dl) was recovered from the plasma. This contained few particles of the size of normal high density lipoprotein and polyacrylamide gel electrophoresis of the lipid-free protein demonstrated a disproportionate increase in the A-II apolipoprotein. All of these abnormalities are consistent with Tangier disease. The serum concentration of glycosphingolipids was approximately 40% lower than normal, with the most marked reductions in the glucosylceramide (GL-1a) and trihexosylceramide (GL-3a) fractions. The relative quantity of long chain fatty acids (23 or more carbons) in serum sphingomyelin was reduced about 38% of that in control sera. Serum lecithin:cholesterol acyltransferase (EC 2.3.1.43; LCAT) activity was 25% of normal and the reduced activity was shown not to be related to a change of enzyme specificity or to a lack of appropriate substrate. These findings are likely related to the HDL deficiency which characterizes Tangier disease. A biopsy sample of apparently normal tonsil contained three to four times the normal amount of cholesterol, and the increase was due entirely to abnormal quantities of cholesteryl esters. Of great interest was the chemical documentation of increased cholesteryl esters in a nerve biopsy specimen. These findings indicate that the neurologic as well as the reticuloendothelial manifestations of Tangier disease may be related to cholesteryl ester accumulation. Lipoprotein profiles, their triglyceride and cholesterol concentration, and LCAT activity were obtained on the plasma of 7 closely related members of the kinship. None of these relatives were found to have the biochemical derangement of Tangier disease.