The effect of corticosteroid administration on the complement independent clearance of IgG sensitized erythrocytes was examined in guinea pigs. 51Cr labeled guinea pig erythrocytes coated with a known amount of high avidity IgG antibody were injected into control and cortisone treated C4 deficient guinea pigs, and cell survival was determined. In these animals with a genetically controlled total deficiency of the fourth complement component, cell bound antibody does not activate the biologically active complement components; clearance is therefore complement independent. At low levels of sensitization, cortisone completely inhibited the splenic sequestration of IgG coated red cells. As the amount of antibody coating the red cell was increased higher cortisone doses were required to decrease the rate and magnitude of clearance. Eventually a level of erythrocyte sensitization was reached where cortisone did not significantly alter the clearance pattern compared to untreated controls. The cortisone effect was present by 3 days but required 5-7 days before it was maximal. No evidence was found to suggest that cortisone decreased the affinity of the antibody for the red cell membrane. Rather, the most likely explanation for these results is that cortisone affects the interaction between IgG on the erythrocyte surface and its receptor on splenic and hepatic macrophages. This experimental model of immune hemolytic anemia parallels those cases of warm antibody mediated disease in which complement plays no role. These findings suggest that a major clinical effect of cortisone therapy may be to decrease complement independent erythrocyte clearance, thereby inducing a remission even in the presence of a positive antiglobulin test.