A T-cell clone (Lyl-03) derived from BALB/cBy mice, though highly specific for OVA/A^d, reacted to allogeneic spleen cells of 6 of 12 H-2 haplotypes tested. The reactivity to each particular H-2 haplotype required the expression of a non-major histocompatibility complex (MHC) gene product present on the B cells of certain strains of mice. All the alloreactive responses were MHC restricted and were inhibited by class II-specific and L3T4-specific monoclonal antibodies. The non-MHC gene product, X, is a new lymphocyte-stimulating determinant that is not expressed in mice with the xid defect. We favor a model that proposes two independent sites (or receptors) for X and the class II molecule. Contrary to previous models for alloreactivity, the anti-MHC site is not directed to a polymorphic receptor for self-class II epitope on the foreign class II molecule, but rather to a conserved determinant present on both self- and allo-class II molecules. If there is only one antigen receptor on the T-cell clone Lyl-03, then anti-X receptor must bind to a cross-reactive determinant found on immunogenic OVA and the non-MHC coded gene product expressed on the cell surface membrane. We further postulate that class II plus “X” recognition may be a general rule for alloreactive as well as autoreactive responses. Thus, both allo-class II and allo-class I reactive T cells are similar in that both bind a non-MHC coded gene product prior to activation.