Host defense against mycobacterial infection requires the participation of monocytes and T cells. Both CD4+ and CD8+ T cells have been shown to be important in resistance to mycobacterial infection in vivo. The main contribution of CD4+ T cells to the protective antituberculosis response involves the production of Th1-type cytokines, including interleukin-2 (IL-2) and gamma interferon (IFN-gamma). CD8+ T cells have been considered to be responsible primarily for cytotoxicity mediated by toxic molecules, including perforin. CD8+ T cells may also elaborate Th1-type cytokines, such as IFN-gamma, in response to the infection. To elucidate the contribution of perforin-mediated target cell death to the control of mycobacterial infection in vivo, mice with a disruption in the perforin gene (P-/-) were infected with Mycobacterium bovis BCG or M. tuberculosis Erdman for 5 and 13 weeks, respectively. At 1, 3, 5, and 13 weeks postinfection, the number of viable mycobacteria in the lungs, spleens, and livers of mice were determined by CFU assay. The infected tissues were examined histologically, and cytokine mRNA levels in the spleens of these mice were determined. Similar studies were carried out in Fas receptor-defective (CBA/lpr(cg)) mice to evaluate the contribution of this alternative cytotoxic pathway to the control of mycobacterial infection. The absence of either perforin gene function or Fas receptor gene function did not modify the course of experimental mycobacterial infection in these mice. In addition, both P-/- and Fas receptor-defective mice appeared to have a compensatory activation of cytokine genes, even in the absence of the experimental infection. P-/- mice had a mean 3.4- to 5-fold increase in mRNA levels for IL-10, IL-12p35, IL-6, and IFN-gamma. Similarly, Fas receptor-defective mice had a mean 3- to 3.6-fold increase in mRNA levels for IFN-gamma, IL-12p35, and IL-10. Our results indicate that both perforin-mediated cytotoxicity and Fas-mediated cytotoxicity do not appear to be necessary for the early control of mycobacterial infection in vivo.