Background: The variability of the efficacy of M. bovis strain BCG used as a vaccine, and the controversial success of M.vaccae as an immunotherapeutic agent, lead the TB community to distrust these means to confront the resurgent TB problem. In addition, it is widely assumed that humoral antibodies against TB play only a minor role during mycobacterial infections. Materials and Methods: To shed some light on the reason for the observed failure of these immunological reagents, we analyzed the humoral immune response against the whole cells and the lysed cells of mycobacterial species M. tuberculosis, M.avium, M.paratuberculosis, M.vaccae and M.phlei, with antibodies raised against a pathogenic TB strain, against avirulent TB strain H37Ra, against A60 of BCG strain Pasteur GL-2 and against BCG strain Copenhagen. The reactivity of the thermostable macromolecular antigens (TMA) of BCG, M. paratuberculosis, M. phlei and M. vaccae, and of LAM extracted from BCG strain Pasteur GL-2 were also analyzed with these antibodies. The cellular immune activity of M. vaccae versus M. bovis strain BCG Pasteur GL-2 was analyzed by their capacity to induce an experimental arthritic syndrome. Results and Conclusions: Our results were that: 1- the serological response obtained by whole cells and lysed cells of M. vaccae appeared most closely related to M. tuberculosis while that obtained by the cells and lysed cells of M .phlei was the most different. However, the antibodies directed against the antigen 60 complex of BCG strain Pasteur GL-2 did not react immunologically very strongly with the lysed cells and the TMA of M.vaccae, 2- the antibodies against pathogenic TB cells, BCG sonicate strain Copenhagen and A60 from BCG Pasteur GL-2 recognized well whole cells and lysed cells of the BCG strains Copenhagen and Pasteur GL-2 but reacted poorly with the whole cells and lysed cells of a pathogenic TB strain and very poorly with the whole cells and lysed cells of BCG strain Aventis-Pasteur currently used as a vaccine (Monovax), 3- the LAM extracted from BCG strain Pasteur GL-2 was poorly recognized by monoclonal antibody CS-40 directed against the LAM of Virulent TB strain Erdman but was recognized by monoclonal CS-35 antibody, that recognizes all LAMs. This LAM was recognized with the same efficacy by the four anti-mycobacterial antibodies used, including antibodies against the A 60 complex of BCG, 4- the cell lysate and the TMA of M. vaccae did not stimulate as effectively the cellular immunity in vivo as did BCG extracts, as shown by their failure to induce an experimental arthritic syndrome under conditions that allowed its induction by the cell lysate and antigen 60 (TMA) of BCG. (Tanaffos 2004; 3(12): 7-18)