Intraperitoneal infection of mice with Mycobacterium lepraemurium produced a primary immune response as represented by direct (IgM) plaque-forming cells at the splenic level within a short period after infection. This response was enhanced when animals were administered a second infection fifteen days after the first one. An identical situation was observed with the developed (IgG) plaques, although the magnitude of these plaques in animals given the second challenge was of a higher order than those given only one infection. In both instances, the number of plaques declined within a very short time after reaching a peak. Higher levels of both direct and developed plaques in animals given second infection was a consequence of the dual effect of antigenic stimulus offerred through the extracellular organisms in the second challenge and intracellular organisms from the previous challenge. The rapid decline, indicated a dampening of the immune response through restricted antigenic stimulus, not only due to all organisms becoming intracellular during the course of infection but also due to structural alterations in the spleens, caused by extensive proliferation of the infecting pathogen. Comparative analysis of the humoral immune response in animals infected with M. leprae, M. marinum and M. lepraemurium indicated similarities in terms of the latent period of induction and decline of the immune response and some very distinct differences in other respects. These differences could be attributed to various factors, such as the site and dose of infection, nature of the disease induced in the animal hose and the ability of the respective organisms to become intracellular. Based on these observations, it is suggested that neither the M. lepraemurium nor the M. marinum models can fully satisfy the requirements, at least immunologically, needed to consider these models as possible substitutes for evaluation of the host-parasite interactions in M. leprae infection of mice, although such a concept has been proposed previously, especially in regard to the M. marinum model.