Background: Toxic epidermal necrolysis is a severe reaction with skin involvement induced by different drugs and other agents. The mechanisms implicated in the induction of the reaction are poorly understood. Objective: Our purpose was to study the involvement of T lymphocytes and other immunocompetent cells in the peripheral blood, blister fluid, and affected skin of 3 patients who had a severe reaction after receiving anticonvulsant medication. Methods: Quantification of T lymphocytes expressing the skin-homing receptor (cutaneous lymphocyte-associated antigen [CLA]) in peripheral blood, skin, and skin blister fluid and assessment of other adhesion molecules, activation markers, and inflammatory interleukins by flow cytometry, immunohistochemistry, and reverse transcription–PCR. Results: An increase in CD3⁺CLA⁺ cells paralleling the severity of the disease was observed in both peripheral blood and skin, tending to normalize as soon as patient’s conditions improved. E-selectin was detected in endothelial vessels in parallel with CLA expression on lymphocytes. An overexpression of TNF⍺, IFN-γ, and IL-2 was also observed in PBMCs. The expression of the different markers changed over the course of the disease. Conclusions: These data show an increase in activated T cells expressing the skin-homing receptor in both tissue and peripheral blood accompanying clinical symptoms, with a recruitment of macrophages and an overexpression of cytokines. All these results suggest an important role for T cells in the production of toxic epidermal necrolysis. (J Allergy Clin Immunol 2000;105:157-65.)