Cross-reactivity between Mycobacterium lepraemurium (MLM) and BCG vaccine was found and evaluated in vivo, in C57BL/6 mice, in terms of delayed-type hypersensitivity, local granulomatous response at the injected site and limitation of growth of the challenge inoculum in the draining node. Cross-reactive specific protection and local reactivities were transferred in syngeneic normal recipients by means of non-adherent lymphoid cells from immune donors. When BCG vaccine was injected either intravenously or subcutaneously in C57BL/6 and in C3H mice, it was able to induce resistance to local infection with living MLM in both strains, but no alteration of the local granulomatous reaction (equivalent to local specific immune response) was observed in C3H mice, as compared to the control. When mice were immunized with one or two injections of heat-killed MLM after the immunomodulating effect of BCG vaccination, better immunization was not achieved. In order to test the presence of strain-related immunosuppressive mechanisms, mice were cyclophosphamide-treated during the immunization process. As expected, higher specific DTH reactions were obtained in both strains, but with only a slight increase of the protective mechanism. Protection was always higher in C57BL/6 than in C3H mice. The specific and non-specific immune responses to BCG vaccine were then evaluated in both strains with different parameters: in vivo lymphoproliferative response in the draining node, delayed local granulomatous reaction at the injected site after a subcutaneous injection, increase in spleen index, kinetics of the immunopotentiation to a thymus-dependent antigen (sheep red blood cells) after a single intravenous injection of BCG. A striking interstrain difference was observed; C57BL/6 mice were able to mount a more rapid and marked immune response as compared to C3H mice (which only developed a delayed and slight response). Moreover, these differences were associated with the fact that BCG did not seem to multiply properly in C3H mice during the first two weeks after inoculation. Thus, it was concluded that higher natural resistance to pathogens and cross-reactive preimmunization with related microorganisms can interfere with the artificial immunization when living microorganisms are used. Implication for vaccination to mycobacterial infection (tuberculosis and leprosy) are discussed.