The effect of hepatic iron on the uptake of ferritin was studied by perfusing livers from normal, irondeficient and iron-loaded rats with 1P61-labeled ferritin. Unlabeled ferritin with tracer doses of labeled ferritin in concentrations of 0.02 to 2,700 nmol/L were studied. Rats were made iron deficient by feeding an established iron-deficient diet for 3 wk. Rats were iron loaded by injection of iron dextran (50 mg/wk) for 3 wk. The mean percentage of uptake of ferritin was similar for doses ranging from 0.22 to 22.2 nmol/L of la61-labeled ferritin. Uptake of ferritin in the normal animal was saturable, with an apparent maximal velocity of uptake of approximately 9.1 pmol/gm/min and a Michaelis-Menten constant of approximately 5 nmoUL at 37" C. Uptake was minimal at 4' C. The mean uptake of ferritin was 78% f 10% in the iron-deficient rats (mean hepatic iron = 1.5 pmoUgm), 79% f 10% in the normal animals (mean hepatic iron = 9.2 pmol/gm) and 78% 2 8% in the iron-loaded animals (mean hepatic iron = 192 pmol/gm). In this experimental system, modulation of hepatic iron did not affect uptake of ferritin, suggesting that regulation of the hepatic ferritin receptor may not depend on hepatic iron content. The rapid uptake of ferritin by the liver despite iron overload is consistent with other observations of the nonregulation of non-transferrimbound iron by hepatic iron and may play a role in the progressive iron overload seen in hemochromatosis.