We report about a brother and sister having clinical symptoms similar to those of homozygous familial hypercholesterolemia (FH) but surprisingly who have normal low density lipoprotein (LDL) receptor activities (M. Harada-Shiba et al, J Jpn Atheroscler Soc 1991; 19:227-242). The LDL receptor activities in the cultured fibroblasts of the patients were compared with those of FH heterozygotes and homozygotes for the LDL receptor mutation. The LDL receptor activities in the cultured fibroblasts of the patients were in the normal range, but their plasma cholesterol concentrations were similar to patients with homozygous FH. After the plasma LDL was removed by plasmapheresis in both patients, plasma cholesterol levels started to increase. The "rebound" of plasma cholesterol was compared with those for heterozygous and homozygous FH. The plasma cholesterol levels of the patients, which were greater than 410 mg/dl 2 weeks after plasmapheresis, were much higher than those of FH heterozygotes (232-311 mg/dl) but similar to those of FH homozygotes (345-464 mg/dl). The urinary mevalonate excretion rate, which reflects the rate of whole-body cholesterol synthesis, was higher for the brother (patient 1, 32.6 nmol/kg.day-1) than for the normal subjects (17.7 +/- 4.1 nmol/kg.day-1) but was similar to those of FH homozygotes (31.2 +/- 4.3 nmol/kg.day-1) and heterozygotes (29.8 +/- 10.9 nmol/kg.day-1). To estimate the catabolic and production rates of cholesterol in the brother, the time course for the increment in the total cholesterol level after plasmapheresis was analyzed by the two-compartment model.(ABSTRACT TRUNCATED AT 250 WORDS)