Coculture of a series of anti-DR1Dw1 alloreactive human T-cell clones with autologous (DR4Dw4/DRw13Dw19) antigen-presenting cells and a series of recall antigens revealed that two of four clones tested proliferated in response to Candida albicans. One was restricted by DR4Dw4 and the other was restricted by DRw13Dw19. These results provide further evidence that many alloreactive T cells have a primary self-restricted specificity and cross-react on allogeneic major histocompatibility complex products. Structural comparison of the responder and stimulator DR molecules for these clones revealed that the regions predicted to contact the T cells' receptor, and thereby to determine self-restriction, are identical in sequence for DR4Dw4 and DR1Dw1 and differ by one residue between DRw13Dw19 and DR1Dw1. The DR beta residues that differ between responder, DR4Dw4 and DR13Dw19, and stimulator, DR1Dw1, are predicted to contribute to antigen binding. This implies that these anti-DR1 T cells may be specific for endogenous peptides that are bound by DR1 and not by the responder DR products, seen in a self-restricted manner. These T-cell clones also cross-reacted on DR4Dw13 and DRw14Dw16 molecules and on a human/murine hybrid class II dimer DR1 beta/I-E alpha. These reactions are discussed in terms of self-restricted peptide recognition. Thus these data suggest that in certain responder/stimulator combinations allorecognition may resemble self-restricted recognition of fragments of endogenous antigens that are bound by stimulator but not by responder major histocompatibility complex products.