CD4(+)CD25(+) regulatory T cells (Treg) play a central role in the prevention of autoimmunity and in the control of immune responses by down-regulating the function of effector CD4(+) or CD8(+) T cells. The role of Treg in Mycobacterium tuberculosis infection and persistence is inadequately documented. Therefore, the current study was designed to determine whether CD4(+)CD25(+)FoxP3(+) regulatory T cells may modulate immunity against human tuberculosis (TB). Our results indicate that the number of CD4(+)CD25(+)FoxP3(+) Treg increases in the blood or at the site of infection in active TB patients. The frequency of CD4(+)CD25(+)FoxP3(+) Treg in pleural fluid inversely correlates with local MTB-specific immunity (p<0.002). These CD4(+)CD25(+)FoxP3(+) T lymphocytes isolated from the blood and pleural fluid are capable of suppressing MTB-specific IFN-gamma and IL-10 production in TB patients. Therefore, CD4(+)CD25(+)FoxP3(+) Treg expanded in TB patients suppress M. tuberculosis immunity and may therefore contribute to the pathogenesis of human TB.