Human Leukocyte Antigens (HLA) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen (Ag)-binding cleft, thereby diversifying the repertoire of self- and pathogen-derived peptide Ags selected by different HLA allotypes. A growing number of immunologically-based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Steven-Johnson’s syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility molecule, HLA-B*57:01, and with a relative risk of >1000. We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the Ag-binding cleft and reaching into the F-pocket where a C-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the Ag-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides selection of new endogenous peptides, inducing a dramatic alteration in ‘immunological self’. The resultant peptide-centric ‘altered self’ activates abacavir-specific T-cells, thereby driving polyclonal CD8+ T cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self-peptides. These findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics, perhaps providing a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small molecule drugs, but also suggesting novel pathway for induction of autoimmunity.