Mycobacterium tuberculosis (MTB)-induced T cell responses are depressed in peripheral blood mononuclear cells of persons with newly diagnosed pulmonary tuberculosis (TB), and levels of interferon (IFN)-γ remain low even after completion of antituberculous therapy. Loss of MTB-reactive T cells through apoptotic mechanisms could account for this prolonged T cell hyporesponsiveness. T cell apoptosis was studied in TB patients and healthy control subjects. Both spontaneous and MTB-induced apoptosis (in CD4 and non-CD4 T cells) from TB patients was increased when compared with healthy control subjects, whereas coculture with control antigen (candida) had no effect on T cell apoptosis in either group of study subjects. An inverse correlation existed between increased MTB-induced T cell apoptosis and IFN-γ and interleukin (IL)-2 immunoreactivities. Successful antituberculous chemotherapy resulted in a 50% reduction in both spontaneous and MTB-induced apoptosis, which coincided with 3- and 8-fold increases in levels of MTB-stimulated IL-2 and IFN-γ, respectively. These data indicate that apoptotic pathways are operant during active MTB infection and may contribute to deletion of MTB-reactive T cells and the immunopathogenesis of this disease.