Many studies have suggested that T cells can recognize totally unrelated peptides and a new term, poly-specificity was coined to express the high specificity of T cell receptors to unrelated peptides [6] . The ''unrelatedness'' of the peptides was defined as low sequence identity, however, sequence identity might not be able to account for the total amount of structural similarity that drives TCR recognition. Here, we demonstrate that this is indeed the case: T cell receptors recognize biochemically and structurally related peptides and cross-reactivity is, up to a degree, predictable. The loss of recognition simply depends on the number and similarity of non-identical amino acid between cross-reactive constituents. We find that the majority of the seemingly ''unrelated'' cross-reactive peptides have a significantly higher biochemical similarity to each other than what would be expected from truly ''unrelated'' peptides. This is especially true for peptides with very limited identity. To our knowledge this is the first study that analyzes a large set of cross-reactive peptide-MHC combinations and demonstrates that the cross-reactivity can, up to a certain extent, be predicted.