Most T cells have T cell receptors (TCR) of micromolar affinity for peptide-major histocompatibility complex (MHC) ligands, but genetic engineering can generate TCRs of nanomolar affinity. The affinity of the TCR used, m33, for its cognate non-self peptide–MHC-I complex (SIYRYYGL-K^b) is 1,000-fold higher than of the wild-type TCR 2C. The affinity of m33 for the self-peptide dEV-8 on K^b is only twofold higher. Mouse CD8⁺ T cells transduced with an m33-encoding retrovirus showed binding of SIY-K^b and potent function in vitro, but in vivo these T cells disappeared within hours after transfer into syngeneic hosts without causing graft-versus-host disease (GVHD). Accordingly, in cases where such CD8-dependent self-reactivity might occur in human adoptive T cell therapies, our results show that a peripheral T-cell deletion mechanism could operate to avoid reactions with the host. In contrast to CD8⁺ T cells, we show that CD4⁺ T cells expressing m33 survived for months in vivo. Furthermore, the m33-transduced CD4⁺ T cells were able to mediate antigen-specific rejection of 6-day-old tumors. Together, we show that CD8⁺ T cell expressing a MHC class I-restricted high-affinity TCR were rapidly deleted whereas CD4⁺ T cells expressing the same TCR survived and provided function while being directed against a class I-restricted antigen.