Although, as yet, there is no specific treatment of epidermolysis bullosa (EB) simplex, anecdotal reports suggest the possible efficacy of one of the newer topical nonsteroidal anti-inflammatory agents, bufexamac. To determine whether bufexamac has any role in the management of this disease, a double-blind placebo-controlled crossover clinical trial was undertaken with ten patients (nine, Weber-Cockayne variant; one, generalized EB simplex). Each of the two preparations was applied four times daily during the 2 four-week treatment periods. Weekly assessments included counts of blisters, crusts, and erosions, and assessments of alterations in cutaneous pain, healing times, and activity times before further blister formation. Although considerable variability in individual responses was noted, no significant difference was detectable between the active drug and its matched placebo. On the basis of these findings, it was concluded that 5% topical bufexamac is ineffective in the treatment of EB simplex.