An alloreactive T-helper-cell line [(A.TH X Balb/c) anti-A.TL] was shown to recognize both H2-Ek and H2-Ed. Both proliferation and polyclonal B-cell activation (protein A plaques) were used in the analyses of specificity. On cloning, the H2-Ek/Ed cross-reaction was shown by one clonotype. This cross-reaction is interpreted in light of the P. Matzinger and M.J. Bevan model (Cell. Immunol. 29, 1, 1977) for antigen recognition by T cells. The antigen recognized was a cell surface non-major histocompatibility (MHC) (minor) alloantigen, shared by the DBA and B10 backgrounds, whose recognition was H2-Ed restricted. This clone is therefore both alloreactive and self-MHC (Ed) restricted minor reactive. Other clones from the cell line were either allospecific or autoreactive. It was shown by antibody blocking that the H2-E alpha (Ia7) determinants involved in the cross-reactive and allospecific recognition were not the same. By antibody blocking it was also shown that the antigenic determinant recognized by the autoreactive clone included H2-Ed. The alloreactive cell line therefore contained three H2-E-reactive clonotypes: allo-Ek specific, H2-Ek and DBA/B10 minor plus H2-Ed cross-reactive, and Ed-associated autoreactive.