The role of CD8+ and CD4+ cells in the generation and maintenance of high-dose oral tolerance has been investigated. Mice depleted of CD8+ cells prior to or subsequent to oral tolerization with OVA continued to express suppressed humoral and/or T cell proliferative responses to the homologous antigen. To assess the effect of CD4+ cell depletion on oral tolerance, mice were depleted of CD4+ cells prior to or subsequent to oral tolerization with OVA. After 50% regeneration of CD4+ cells was achieved, OVA-immunized mice produced anti-OVA immune responses that were comparable to those of water-fed control mice. Thus, under our experimental conditions the presence of CD4+ but not CD8+ cells is required to both establish and maintain oral tolerance.