A new case of homozygous familial hypobetalipoproteinemia is reported in a 16-yr-old girl. Apoprotein B was absent from plasma and the patient had acanthocytes and steatorrhea, but minimal neurologic dysfunction. Total body cholesterol synthesis was assessed intermittently over a 30-mo period by sterol balance techniques. The rate of synthesis of cholesterol was higher (15.0 +/- 2.9 mg/kg/day) in the patient (8.3 +/- 0.4 mg/kg/day than in 3 control children, p less than 0.005). Bile acid synthesis was similar (4.6 +/- 1.8 versus 4.0 +/- 1.7 mg/kg/day) in the patient and controls, but total body sterol synthesis was significantly higher (19.6 +/- 3.0 versus 12.2 +/- 2.0, p less than 0.005). The absorption of orally administered [1,2,(3)H] cholesterol in the patient was low and less than 0.5% of the label appeared in the total plasma volume at all times up to 48 hr. Estimates of the extent that malabsorption of biliary cholesterol contributes to the enhanced excretion of neutral sterols in this case indicate that all of the increase can be explained on this basis. Thus, although the mechanisms for the increased sterol synthesis in this case may relate to the absence of chylomicrons and low density lipoproteins in plasma, the magnitude of the increase can be fully explained on the basis of a compensatory mechanism to maintain cholesterol homeostasis in the face of enhanced fecal losses.