Productive engagement of T cell receptors (TCRs) by cognate ligand (major histocompatibility complex plus peptide) leads to proliferation, differentiation, and the elaboration of effector functions. Altered peptides generated by single amino acid substitutions in the antigenic peptide have diverse effects on the outcome of the T cell response. We have generated an altered peptide (Q144) from an autoantigenic peptide of myelin proteolipid protein 139–151 by a single amino acid substitution (from tryptophan to glutamine) in the primary TCR contact at position 144 that is capable of inducing CD4⁺ T cell responses in H-2^s mice. By using a Q144-specific T cell clone (Q1.1B6), we see a hierarchy in T cell proliferation and cytokine production with various position 144 substituted peptides and have identified a peptide (L144) that hyperstimulates this T cell clone. In contrast to Q144, L144 induces maximal proliferation at 7 logs lower antigen concentration, induces greater cell death at higher antigen dose, and induces the secretion of cytokines not detected following stimulation with the cognate ligand. This heteroclitic T cell response associated with changes in cytokine profile was observed with several other T cell clones of different specificities. The L144 peptide also induces costimulation independent proliferation and cytokine production from the Q1.1B6 T cell clone. We describe this as a superagonist response. Such responses may have a role in the initiation of autoimmunity by promoting a proinflammatory environment following ligation of a cross-reactive TCR on autoreactive T cells.