Peripheral blood lymphocytes from both drug-induced immediate and delayed cutaneous hypersensitivity reactions frequently can be stimulated in vitro with the particular culprit drug. Immunohistochemical analysis has identified CD8+ T cells as the predominant epidermal T-cell subset in drug-induced maculopapular and bullous eruptions and in patch-test reactions to beta-lactam antibiotics. Beta-lactam-specific peripheral and epidermal T lymphocytes from bullous exanthems were predominantly T-cell receptor alpha/beta+, CD8+, CD4-. Three CD8+ epidermal T-cell clones from penicillin-induced bullous exanthems displayed a TH1-like cytokine pattern and proliferated in an antigen- and major histocompatibility complex-specific manner. These epidermal T-cell clones were cytotoxic against autologous B cells upon stimulation through the T-cell receptor and against epidermal keratinocytes in lectin-induced cytotoxicity assays. In contrast, peripheral T-cell lines from patients with penicillin-induced urticarial exanthems were predominantly T-cell receptor alpha/beta+, CD4+, CD8- and displayed a Th2-like cytokine pattern. CD8+ dermal T cells from a sulfamethoxazole-induced bullous exanthem proliferated in vitro in response to sulfamethoxazole. This T-cell proliferation was significantly increased in the presence of microsomes, which suggests that microsomal enzymes, such as cytochrome P450 enzymes, generate highly reactive metabolites which are the nominal antigens for T-cell activation. In summary, drugs may be processed and presented in different ways, which is reflected by the observation that Th1-like CD8+ T cells are primarily activated in delayed cutaneous hypersensitivity reactions, whereas Th2-like T-cell responses are present in patients with drug-induced urticarial exanthems.