Regulatory T cells are critical in regulating the immune response, and therefore play an important role in the defense against infection and control of autoimmune diseases. However, a therapeutic role of regulatory T cells in an established disease has not been fully established. In this study, we provide direct evidence that CD4+ CD25+ regulatory T cells can cure an established, severe, and progressive colitis. SCID mice developed severe colitis when adoptively transferred with naive CD4+ CD25− T cells and infected with the protozoan parasite Leishmania major. The disease development can be completely halted and symptoms reversed, with a healthy outcome, by transferring freshly isolated or activated CD4+ CD25+ T cells from syngeneic donors. The therapeutic effect of the regulatory T cells was completely blocked by treatment of the recipients with anti-IL-10R, anti-CTLA4, or anti-TGF-β Ab. However, the resurgence of colitis under these treatments was not accompanied by the reactivation of Th1 or Th2 response nor was it correlated to the parasite load. These results therefore demonstrate that CD4+ CD25+ T cells are therapeutic and that the effect is mediated by both IL-10/TGF-β-dependent and independent mechanisms. Furthermore, colitis can manifest independent of Th1 and Th2 responses.