Recombinant murine Gamma interferon (rIFN-gamma) causes powerful inhibition of M. tuberculosis by murine peritoneal macrophages. This inhibition is totally abrogated by glucocorticosteroid hormones. In contrast, glucocorticoids do not oppose the weak inhibition of M. tuberculosis by human macrophages which can be induced with human rIFN-gamma, nor do they reduce the effect in this system of 1,25-(OH)2 vitamin D3. However, glucocorticoid hormones do decrease the baseline inhibition of M. tuberculosis exerted by monocytes from some normal human donors without any preincubation in an activating stimulus. Thus there is a steroid-sensitive anti-mycobacterial mechanism in human macrophages, but IFN-gamma is not the lymphokine which induces it. We suggest that this mechanism may be important for protection and steroid-induced reactivation, and deserves further study. On the other hand, the IFN-gamma and vitamin D3 pathway may be more relevant to immunopathology.