INTRODUCTION: Immune mediated adverse drug reactions (IM-ADRs) pose a significant risk to human health, and often occur more frequently in subjects expressing certain HLA molecules. One of the strongest such genetic association has been described for the drug abacavir. Hypersensitivity syndrome induced by abacavir is driven by drug-specific activation of cytokine producing, cytotoxic CD8+ T cells exclusively found in individuals expressing the HLA-B*57:01 allele variant. Abacavir interacts with the peptide binding cleft of the HLA-B*57:01 molecule, thus increasing the affinity of certain self-peptides generating an altered self-peptide repertoire. The hypothesis is that other IM-ADR causing drugs could work through a similar mechanism. OBJECTIVE: Investigate four IM-ADR causing compounds with strong known HLA association (allopurinol/oxypurinol with HLA-B*58:01, flucloxacillin with HLA-B*57:01, nevirapine with HLA-DRB1*01:01) to determine if they cause an altered self-peptide repertoire like abacavir. METHODS: MHC binding assays and MHC ligand elution studies established in the abacavir system were systematically applied to determine if drug specific effects on the binding specificity of these molecules are detectable. Each assay was run in a side-by-side setup in the presence vs. absence of a drug which allowed for direct comparison of the results. RESULTS: While in the presence of abacavir significant increases in binding affinity (up to 1,000-fold) of peptides with small hydrophobic C-terminal residues (valine, isoleucine, leucine) to the HLA-B*57:01 molecule had been observed, no such effect was found for the drugs and their IM-ADR-associated HLA molecule investigated in the current study. Consistent with the binding results, peptide elution studies utilizing HLA-B*57:01 single transfected cells performed in the presence of abacavir had shown an elevated number of endogenously bound peptides with a C-terminal, small hydrophobic residue. However, elution studies performed here with four additional compounds showed no difference in the eluted peptide profile in the presence vs. absence of a drug. CONCLUSION: The drug:MHC interactions investigated in this study likely function through a different mechanism from abacavir.