To demonstrate the lability of drug binding, drug specific T cell lines, T cell clones and TCR hybridoma cells were required. Washing of the cell mix of drug, APC and T cells abrogated p-i reactivity, while T cell reaction to haptens persisted. The presentation of peptides by HLA on APC takes > 4hr pulsing (uptake of hapten modified protein, processing and presentation), and may also require metabolism, if the stimulating drug was chemically inert and not a hapten. Therefore, an immediate reactivity of T cells (e.g. measured by rapid Ca influx) as well as reactivity to the drug in the presence of protein and metabolism inhibitors or by using glutaraldehyde-fixed antigen presenting cells was interpreted as p-i reaction. P-i reactivity was demonstrated for a number of drugs (SMX, lidocain, lamotrigine, carbamazepine, various radio contrast media, quinolones, vancomycin, dapsone, etc.), including some drugs which can act via p-i or as hapten (piperacillin, flucloxacillin, amoxicillin, cephalosporins, monobactams). In these cases the p-i reactivity was responsible for more severe reactions like hepatitis in flucloxacillin/B*57:01 carriers or DRESS with amoxicillin and piperacillin