The term bullous drug eruption connotes several heterogeneous diseases in which blisters occur as a complication of the administration of drugs. Blisters may occur in bullous erythema multiforme, fixed drug eruption, or severe dermatitis medicamentosa with blisters. The common denominator is thought to be a hypersensitivity reaction to a systemic medication. Nevertheless, little has been written about the blisters in these disorders, and neither common nor distinct pathogenic mechanisms have been proposed. We describe a patient who had a rapidly progressive bullous eruption that occurred within hours of receiving intravenous trimethoprim-sulfamethoxazole. Routine histologic study of lesional skin demonstrated subepidermal blisters. Transmission electron microscopy and immunomapping of various basement components revealed that the cleavage plane of the blister was well below the lamina densa. After healing of the blistering process, no scarring or milia formation was observed.