Tuberculosis (TB) remains a global health problem. The solution involves development of an effective vaccine, but has been limited by incomplete understanding of what constitutes protective immunity during natural infection with Mycobacterium tuberculosis. In this study, M. tuberculosis-specific responses following an overnight whole-blood assay were assessed by intracellular cytokine staining and luminex, and compared between TB cases and exposed household contacts. TB cases had significantly higher levels of IFN-gamma(+)TNF-alpha(+)IL-2(+)CD4(+)T cells compared with contacts. TB cases also had a significantly higher proportion of cells single-positive for TNF-alpha, but lower proportion of cells producing IL-2 alone and these differences were seen for both CD4(+)and CD8(+) T cells. Cytokine profiles from culture supernatants were significantly biased toward a Th1 phenotype (IFN-gamma and IL-12(p40)) together with a complete abrogation of IL-17 secretion in TB cases. Our data indicate that despite a robust response to TB antigens in active TB disease, changes in the pattern of cytokine production between TB infection and disease clearly contribute to disease progression.