The induction of peripheral tolerance following oral antigen administration in several autoimmune disease and conventional animal models correlates with the production of transforming growth factor‐β (TGF‐β) and T helper type 2 (Th2) cytokines. The factors regulating TGF‐β production and its relation to the Th2 response, however, have not been defined. We demonstrate that the systemic administration of antibodies to interleukin (IL)‐12 to ovalbumin (OVA)‐T cell receptor (TCR) transgenic mice fed high doses of OVA, followed by systemic OVA challenge, substantially enhances TGF‐β, but not IL‐4 production by peripheral T cells. Furthermore, we demonstrate in an in vitro T cell differentiation model that naive (CD4⁺/Mel‐14^hi) OVA‐TCR‐T cells stimulated with OVA‐pulsed dendritic cells (DC) produce four‐to fivefold higher amounts of TGF‐β when cultured with anti‐IL‐12 or anti‐interferon‐γ (IFN‐γ). In this in vitro system, IL‐4 was not required for TGF‐β production by T cells; however, it appeared to enhance levels of TGF‐β by promoting the growth of TGF‐β‐producing cells. Our findings demonstrate that IL‐12 and IFN‐γ are important negative regulators of TGF‐β production both in vivo and in vitro, and that their modulation may be of benefit for the treatment of autoimmune disorders.