The venom from the brown recluse spider, Loxosceles reclusa, contains one or more factors which produce skin necrosis. A dermonecrotic factor with sphingomyelinase D activity was purified from the spider's venom sacs which produced skin necrosis when injected intradermally in rabbits. Adsorption of the dermonecrotic activity occurred following incubation with isolated membranes from different cell types or different species in a dose-responsive fashion. Since injection of the complex in rabbits produced skin necrosis, a specific antibody that inhibits the dermonecrotic activity and sphingomyelinase activity was used to identify the venom fraction on the plasma membrane of erythrocytes with electron microscopy. Initiation of cutaneous inflammatory reaction may result from high-affinity interaction of a venom component in the brown recluse spider venom and cell membranes.