Several different mechanisms have been implicated in oral tolerance to protein antigens, depending on the nature and dose of antigen used and the species under study. Here, we have investigated the basis of unresponsiveness in a well-established model of oral tolerance in mice fed 25 mg ovalbumin (OVA). Our results show that CD8+ T-cell activity is suppressed by feeding OVA and that these cells are not required for the induction of tolerance. CD4+ T cells are essential for tolerance to occur, but both Th1 and Th2 cell-dependent functions are tolerized equally in OVA-fed mice. Peripheral lymph node cells from tolerized mice rapidly undergo apoptosis when cultured in vitro but produce substantial amounts of transforming growth factor β (TGFβ) in response to OVA. The appearance of tolerance in vivo is preceded by a transient phase of T-cell priming, and we propose that this model of oral tolerance reflects partial activation of T cells by fed antigen, leading to selective production of TGFβ and consequent inactivation of all effector T cells. These findings indicate that the active suppression and clonal anergy identified previously in mice with oral tolerance may not be mutually exclusive phenomena.