Normal CD-1 mice were infected intravenously, subcutaneously, or aerogenically with live bacille Calmette Guerin (BCG) Tice or BCG streptomycin resistant (SM-res) and growth of the organisms in the footpad, the draining popliteal lymph node, the blood, lung, liver, and spleen was followed for as long as 50 days. The vaccinated mice were then challenged on day 50 with 10-5 viable Mycobacterium tuberculosis Erdman organisms introduced intravenously or subcutaneously. The growth of the Erdman challenge was followed in the appropriate organs for the next 20 days. Measurement of tuberculin hypersensitivity was carried out by footpad tests. The BCG Tice introduced aerogenically or subcutaniously into normal mice induced degrees of antituberculous resistance equivalent to those seen earlier in intravenously infected mice. The BCG SM-res was still nonimmunogenic when introduced subcutaneously or by the aerogenic route. Suspension of the organisms in sterile mineral oil before their injection into the footpad slowed their rate of inactivation and marginally increased the immune response seen later in the host. Introduction of BCG SM-res into T-cell depleted mice by the 3 inoculation routes was associated with no marked improvement in the survival of this organism in vivo, suggesting that BCG SM-res is inactivated in vivo by a nonimmunologically mediated mechanism.