To attempt to resolve the controversy on the role of thymic epithelial cells (TEC) in tolerance induction, athymic mice were grafted with allogeneic day-14 fetal thymuses treated with deoxyguanosine in vitro. The data indicate that the tolerogenicity of TEC varies considerably according to the antigen and the subpopulation of T cells studied. For cytotoxic CD8+ cells responding to H-2 class I antigens, TEC induce minimal tolerance. For proliferative responses of CD4+ cells, by contrast, TEC induce significant tolerance to H-2 class II antigens but no detectable tolerance to Mlsa antigens.