To elucidate the roles of cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4) in oral tolerance, we studied the consequences of CTLA‐4 blockade during the inductive phase of oral tolerance using a transgenic T‐cell transfer model. We found that CTLA‐4 blockade significantly accelerated cell cycle progression of antigen‐specific T cells and dramatically increased their numbers in lymphoid organs following oral administration of ovalbumin (OVA). In mice fed with OVA, only ≈ 35% of specific T cells underwent more than four cycles of cell division. This was increased to 65% in mice fed with OVA and treated with a blocking anti‐CTLA‐4 monoclonal antibody (mAb). The OVA‐specific T cells in the latter group were localized primarily in the T‐cell zones of the mesenteric lymph nodes and Peyer's patches with a few penetrated into B‐cell follicles. Nevertheless, both faecal anti‐OVA immunoglobulin A (IgA) and seral anti‐OVA immunoglobulin G (IgG) were produced in anti‐CTLA‐4 mAb‐treated mice. These results suggest that CTLA‐4 limits the degree of T‐cell activation by blocking cell cycle progression during the inductive phase of oral tolerance. In the absence of the CTLA‐4 signal, mucosal exposure of antigen induces heightened T‐cell activation and expansion, which in turn promotes the production of antigen‐specific antibodies.