We studied 6 patients from 6 different geographic areas who presented with acute flu-like illnesses. The patients developed persistent fevers, lymphadenopathy or diarrhea, pneumonia, and/or heart, liver, or adrenal failure. They died in 1–7 weeks. These patients had no serological evidence of HIV infection and could not be classified as AIDS patients according to CDC criteria. The clinical signs as well as laboratory and pathological studies of these patients suggested an active infectious process, although no etiological agent was found despite extensive infectious disease work-ups during their hospitalization. Postmortem examinations showed histopathological lesions of fulminant necrosis involving the lymph nodes, spleen, lungs, liver, adrenal glands, heart, and/or brain. No viral inclusion cells, bacteria, fungi, or parasites could be identified in these tissues using special tissue stains. We report that immunohistochemistry using rabbit antiserum raised against VLIA, the virus-like infectious agent previously identified in patients with AIDS and shown to cause fatal systemic infection in primates, revealed VLIA antigens in these necrotizing lesions. In situ hybridization using an 35S labeled VLIA-specific DNA probe also detected VLIA genetic material in the areas of necrosis. Furthermore, virus-like particles closely resembling VLIA were identified ultrastructurally in these histopathological lesions. VLIA was associated with the systemic necrotizing lesions in these previously healthy non-AIDS patients with an acute fatal disease.