Toxic epidermal necrolysis and Stevens-Johnson syndrome are severe cutaneous drug reactions of unknown mechanism. Nitric oxide can cause apoptosis and necrosis. The inducible form of nitric oxide synthase generates large amounts of nitric oxide and has been described in human skin. We propose that a large burst of nitric oxide in toxic epidermal necrolysis and Stevens-Johnson syndrome may cause the epidermal apoptosis and necrosis. Skin biopsies were taken from seven patients with actively progressing Stevens-Johnson syndrome or toxic epidermal necrolysis. Expression of inducible nitric oxide synthase was examined by reverse transcription-polymerase chain reaction and by immunoperoxidase staining for inducible nitric oxide synthase protein. Messenger RNA for inducible nitric oxide synthase was detected by reverse transcription-polymerase chain reaction and confirmed by the sequencing of polymerase chain reaction products. Strong staining for inducible nitric oxide synthase was observed in inflammatory cells in the lower epidermis and upper dermis. Diffuse, weaker staining was observed in keratinocytes. Expression of inducible nitric oxide synthase is consistent with the hypothesis that nitric oxide mediates the epidermal necrosis in toxic epidermal necrolysis and provides a potential target for therapeutic intervention.