The clearance of 51Cr labeled guinea pig erythrocytes, sensitized with a known amount of IgM or IgG antibody, was examined in normal and Bacillus Calmette Guerin (BCG) infected guinea pigs. In normal animals, IgM coated cells were rapidly sequestered in the liver. Most of these cells were then slowly released into the circulation where they survived normally as Coombs positive erythrocytes. Neither the site nor extent of initial clearance showed major alterations in BCG infected animals; however, there was no return of the sequestered erythrocytes into the circulation. This pattern of clearance was only seen in normals at very high levels of sensitization. In contrast to the IgM studies, the pattern of clearance of IgG sensitized erythrocytes was not altered, but the rate and magnitude was markedly increased at all levels of sensitization. In addition, complement independent clearance of IgG sensitized erythrocytes was augmented in BCG infected guinea pigs lacking a classical complement pathway function. The spleen remained the organ primarily responsible for this increased clearance of IgG sensitized erythrocytes. Sensitized cells in BCG infected animals were removed from the circulation as if they were coated with several times the amount of antibody. Serum factors were shown to be responsible for the increased clearance. These data suggest that increased macrophage activation in BCG infected animals plays a critical role in determining the consequences of cell sensitization in vivo. These studies may help to explain exacerbations of hemolytic anemias and related states after intercurrent infections.