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Eczema vaccinatum (EV) is a complication of smallpox vaccination that can occur in persons with eczema/atopic dermatitis (AD), in which vaccinia virus disseminates to cause an extensive rash and systemic illness. Because persons with eczema are deferred from vaccination, only a single, accidentally transmitted case of EV has been described in the medical literature since military vaccination was resumed in the United States in 2002. To enhance understanding of EV, we review its history during the era of universal vaccination and discuss its relationship to complications in persons with other diseases or injuries of the skin. We then discuss current concepts of the pathophysiology of AD, noting how defective skin barrier function, epidermal hyperplasia, and abnormal immune responses favor the spread of poxviral infection, and identify a number of unanswered questions about EV. We conclude by considering how its occurrence might be minimized in the event of a return to universal vaccination.