To explore a mechanism of interleukin (IL)‐6–induced hypoferremia in rats, iron metabolism was investigated both in vivo and in vitro. Recombinant IL‐6 was intraperitoneally administered to male Wistar rats and the serial change of parameters related to iron metabolism was examined. After administration of IL‐6, plasma IL‐6 concentration increased rapidly, reached its maximum in 1 hr and thereafter decreased quickly. Plasma IL‐6 3 hr after IL‐6 injection (50 μg/kg) was 3 units/ml, which is a concentration capable of inducing hepatic ¹²⁵I–labeled transferrin uptake in vitro using isolated hepatocytes. Plasma iron concentration and transferrin saturation had decreased to approximately one third of the initial level within 3 hr and then recovered. Total iron binding capacity remained unchanged for 6 hr, then began to decrease. Red blood cell count and hemoglobin concentration showed no remarkable changes during this period. By ferrokinetic study with plasma that contained iron 59–labeled transferrin, the plasma iron disappearance half time, calculated from the disappearance curve, was significantly shortened from 55 min to 22 min by IL‐6 treatment (p<0.01). The ferritin concentration in the liver was increased significantly after the administration of IL‐6 (p<0.001), but transiently decreased in the spleen. The plasma ferritin showed a gradual increase during the 6‐hr period after IL‐6 injection. The uptake of ¹²⁵I‐labeled diferric transferrin by isolated hepatocytes was increased by IL‐6 treatment and this increment was inhibited by addition of 100‐fold excess unlabeled transferrin. On the other hand, no significant increment of ¹²⁵I‐labeled differic transferrin uptake was observed in Kupffer cells. These results confirmed that in rats, IL‐6 produced a rapid increase of hepatic uptake of serum iron by means of transferrin receptor and resulted in hypoferremia. (HEPATOLOGY 1994;19:1468–1475.)