Drug-induced toxic epidermal necrolysis (TEN) is a rare but frequently lethal disease of the skin and mucosa of unknown etiology. Toxic metabolic and immunologic products in the serum have been discussed as possible causes. For this reason we have performed plasmapheresis on these patients for many years. Results regarding survival and healing of the lesions are quite favorable, as exemplified with two patients described here who benefited from the procedure despite their old age. In order to gain insight into possible disease mechanisms that would explain the beneficial effect of plasmapheresis, we did immunohistochemical studies on these patients before and in one case after the procedure. In dermis and epidermis, there was a striking increase of macrophages and a relative increase of CD8-positive lymphocytes which might act as cytotoxic effector cells; these findings can be interpreted as the result of an immunological reaction. An increased staining of lesional epidermis with TNF alpha, as previously noted by other authors, should be interpreted with caution since necrotic cells are involved. On the basis of the clinical results, the pathogenetic considerations, and in view of the lack of specific treatment modalities, clinical studies concerning plasmapheresis for the treatment of toxic epidermal necrolysis are recommended, particularly since this procedure is widely available and generally well tolerated.