To analyze whether and how T cells are involved in drug allergies, we analyzed the drug-induced activation of T cell subsets, T cell receptor V-beta usage and cytokine secretion of T cells from the peripheral blood of drug-allergic individuals. The specificity of the T cells was demonstrated by specific restimulation of drug specific clones. We found that drugs which do not need to be metabolized to become immunogenic (haptens like penicillin G) can stimulate CD4+ and CD8+ T cells in vitro. The T cell response to penicillin can be oligoclonal (use of a certain T cell receptor Vbeta only) or polyclonal. Only polyclonal T cell lines were cross-reactive with other beta-lactam antibiotics. Sulfamethoxazole and lidocaine are thought to gain their ability to bind to proteins by intracellular drug metabolism. They were found to stimulate CD4+ and CD8+ T cells in vitro, and some reactive T cell lines were oligoclonal. The majority of lidocaine-specific clones secreted rather high amounts of IL-5 and IL-4 after PMA/ionomycin stimulations (Th2-like), but some CD4+ and all CD8+ clones had a Th1-like phenotype (high INF-gamma and TNF-alpha). The data clearly demonstrate the existence of drug-specific alphabeta+ T cells in the circulation of drug-allergic individuals and reveal a great heterogeneity of T-cell-mediated responses. Further studies are needed to correlate the type of T cell response to the clinical picture, which can be quite heterogeneous.