The proportions of peripheral blood mononuclear cells (PBMC), CD4(+) T cells, and CD8(+) T cells that produce gamma interferon (IFN-gamma) in response to Mycobacterium tuberculosis were markedly reduced in tuberculosis patients, particularly in those with severe disease. Depletion of CD4(+) but not CD8(+) cells prior to stimulation of PBMC with M. tuberculosis abolished IFN-gamma production. These results show that (i) IFN-gamma production by CD8(+) and CD4(+) cells correlates with the clinical manifestations of M. tuberculosis infection and (ii) IFN-gamma production by CD8(+) cells depends on CD4(+) cells.