With the advent of effective antiviral treatment for disseminated herpes infection it has become important to be able to make a firm clinical diagnosis of this condition. We undertook a retrospective analysis of 20 patients with disseminated herpes simplex infection diagnosed at necropsy to derive useful clinical pointers to this severe form of the disease. The most useful clinical criteria were malnutrition, post measles state, and local herpes infection in addition to encephalopathy, enlarging hepatomegaly, and deteriorating pneumonia. The liver showed characteristic histological changes in 18 of 19 patients. These clinical criteria combined with liver biopsy were applied in a prospective pilot study of five patients at risk for disseminated herpes infection and the results were encouraging.