Many T cell receptors (TCRs) that are selected to respond to foreign peptide antigens bound to self major histocompatibility complex (MHC) molecules are also reactive with allelic variants of self-MHC molecules. This property, termed alloreactivity, causes graft rejection and graft-versus-host disease. The structural features of alloreactivity have yet to be defined. We now present a basis for this cross-reactivity, elucidated by the crystal structure of a complex involving the BM3. 3 TCR and a naturally processed octapeptide bound to the H-2K b allogeneic MHC class I molecule. A distinguishing feature of this complex is that the eleven-residue-long complementarity-determining region 3 (CDR3) found in the BM3. 3 TCRα chain folds away from the peptide binding groove and makes no contact with the bound peptide, the latter being exclusively contacted by the BM3. 3 CDR3β. Our results formally establish that peptide-specific, alloreactive TCRs interact with allo-MHC in a register similar to the one they use to contact self-MHC molecules.