The relationship between tissue steroid measurements and clinical findings was examined in six individuals with cerebrotendinous xanthomatosis. Tendon xanthomas (six of six patients), neurologic dysfunction (four of six), pulmonary insufficiency (four of six), premature atherosclerosis (three of six), cataracts (two of six), and endocrine hypofunction (one of six) were encountered with decreasing frequency. Plasma cholestanol concentrations were elevated and were associated with low plasma cholesterol levels. Fifteen tissues obtained at postmortem contained 10 to 400 times more cholestanol and 30% more cholesterol. In bile, 10 times more cholestanol and substantial quantities of cholesterol precursors were found, but virtually no chenodeoxycholic acid was secreted. These findings indicate that symptoms develop at a variable pace and probably result from tissue accumulation of both sterols. The secretion of cholesterol percursors in the bile and elevated tissue sterol concentrations suggest overactive hepatic sterol synthesis, which we believe is related to a block in chenodeoxycholic acid production.