The course of infection after injection of small doses of bacillus Calmette-Guérin (BCG) was studied in mice which were depleted in vivo of T cell subsets by administration of either anti-L3T4 or anti-Lyt-2 mAb. The results presented herein strongly suggest that the L3T4+ subpopulation play a pivotal role in the immunologic control of BCG infection because the depletion of L3T4+ cells led to a dramatic increase in the number of viable bacteria. Depletion of Lyt-2+ cells had no significant effect on the course of infection. These results were confirmed by using adoptive transfer experiments which showed that protective immunity was mediated by L3T4+ cells generated in the spleen as a result of infection. Moreover, T cells capable of controlling the recurrence of BCG multiplication from residual bacteria remaining in organs after the recovery from infection were shown to belong to the L3T4+ subpopulation.