Adverse drug reactions (ADRs) inflict a significant toll on our health care system, preventing the use of key medications.  A subset of ADRs involve the inappropriate activation of T cells resulting in immune responses targeted against healthy tissues.  The Human Leukocyte antigen (HLA) class I and II molecules are cell surface proteins that present both self and pathogen derived peptides to CD8 and CD4 T cells, respectively.  Under immunogenic conditions, peptides that are not part of the normal self-repertoire (for example pathogen derived peptides) stimulate T cell responses to help combat infection.  Drugs such as beta-lactam antibiotics (including penicillins) have been shown to modify proteins and T cell responses to antigen presenting cells fed with drug modified human serum albumin have been observed.  Here we explore modifications induced by penicillin-G in cell culture media containing either bovine or human serum.  We use these data, in combination with the large amount of HLA-peptide ligand data amassed in the laboratory, to explore the potential for both direct haptenation of, and haptenated peptide presentation by, the HLA molecules.  These data lay the groundwork for screening for drug-modified HLA-peptide complexes.