To study further the pathogenesis of Lucio's phenomenon, we have made a comparative histological study of 11 patients with Lucio's phenomenon and 12 with ENL. Confirming the findings of others, Lucio's reaction could be distinguished from ENL by epidermal necrosis and by necrotizing vasculitis manifesting necrosis in the walls of superficial vessels and severe, focal endothelial proliferation of mid-dermal vessels. Furthermore, in Lucio's phenomenon large numbers of AFB were found in evidently normal and in swollen or proliferating endothelial cells. We hypothesize that patients with Lucio's phenomenon have an exceptionally deficient defense mechanism, allowing unrestricted proliferation of AFB in endothelial cells, facilitating contact between bacterial antigen and circulating antibody and leading to infarction; also, this nadir of resistance allows unimpeded dissemination of AFB, accounting for the clinical features of diffuse non-nodular leprosy. Thus, an explanation is offered for the restriction of Lucio's phenomenon to patients with diffuse non-nodular lepromatous leprosy.