Dextrans and albumin exit brain from blood following intra-cerebral injection by a slow process of convection with a halftime of 10-12 h in the rat. The present studies show that immunoglobulin G (IgG) molecules rapidly efflux from brain to blood across the blood-brain barrier (BBB) following intracerebral injection. The IgG efflux is rapid with a halftime of 48 min in the rat. The efflux of [3H]mouse IgG(2a) from brain to blood is competitively inhibited by intracerebral injection of unlabeled mouse IgG molecules, but is not inhibited by intracerebral injection of comparable doses of unlabeled rat albumin. The IgG efflux system has characteristics of an Fc receptor, as the efflux from brain is competitively inhibited by Fc fragments but is not blocked by F(ab')(2) fragments. Precipitation of brain homogenate by trichloroacetic acid indicates there is no significant metabolism of the IgG molecules during the experimental time period. In conclusion, these studies provide evidence for a BBB Fc receptor that mediates the reverse transcytosis of IgG molecules in the direction of brain to blood.