Human immune responses to M. tuberculosis are characterized by activation of multiple T cell subsets including CD4+, CD8+, and γδ T cells, and the role of CD8+ αβ TCR+ T cells in this response is poorly understood. Stimulation of T cells from healthy tuberculin skin test-positive persons with live M. tuberculosis-H37Ra or soluble M. tuberculosis Ags readily up-regulated IL-2Rα (CD25) expression on CD8+ T cells. Purified resting and activated CD8+ T cells produced IFN-γ and proliferated to both M. tuberculosis bacilli and soluble mycobacterial Ags with monocytes as APC. Precursor frequency of mycobacterial Ag-specific CD8+ T cells by IFN-γ enzyme-linked immunospot was 5–10-fold lower than the precursor frequency of CD4+ T cells, and IFN-γ secretion by CD8+ T cells was 50–100-fold lower. CD8+ T cells secreted∼ 10-fold less IFN-γ per cell than CD4+ T cells in response to mycobacterial Ags. CD8+ T cell responses to M. tuberculosis bacilli were blocked by anti-MHC class I antibody and required Ag processing. Processing of M. tuberculosis bacilli by monocytes for presentation to MHC class I-restricted CD8+ T cells was insensitive to brefeldin A treatment, which blocks the conventional MHC class I Ag-processing pathway. These results represent the first demonstration that human cells can process pathogen Ags via an alternate Ag-processing pathway for MHC class I and suggest a mechanism for participation of IFN-γ-secreting CD8+ T cells in the human immune responses to M. tuberculosis.