Summary The present studies are concerned with the role of macrophages in antibody production to sheep red blood cells (SRBC). Intact thioglycollate (TG)-induced SRBC-containing peritoneal cells elicited antibodies in normal syngeneic recipient mice but not in irradiated mice. This suggests the release of immunogens by the antigen-carrying macrophages, inducing an immunologic response with kinetics similar to that after injection of non-phagocytized SRBC. Simultaneous administration of 15 million TG-induced peritoneal cells and SRBC did not decrease the immunogenicity of the SRBC. These results suggest that macrophages are not merely “scavenger” cells, and that the macrophage does not play a negative role in the immunization process. Mice exposed to SRBC 5 days after injection of TG, when their internal production of macrophages was maximal, exhibited an impaired immune response to threshold doses of SRBC. The significance of these results was discussed. Comparison of the persistence of immunogenicity of intracellular SRBC in vitro and in vivo suggests that the sharp decrease in immunogenicity in vitro is unphysiological.