The purpose of this study is to document three cases of fatal measles infection in children who ranged in age from 1 to 6 years old. In each case, there was a rapidly progressive illness marked by severe respiratory and central nervous system disease; in two cases, tonsillar herniation occurred. The lung tissues showed marked interstitial pneumonitis with diffuse endothelial cell and pneumocyte degeneration; occasional multinucleated giant cells were observed. Brain sections showed a paucicellular inflammatory infiltrate with diffuse neuronal damage. Measles nucleoprotein and measles RNA were detected in each case by immunohistochemistry and reverse transcriptase (RT) in situ PCR, respectively. In the lung tissues, the viral protein and RNA localized primarily to pneumocytes and macrophages; infected endothelial cells were also evident. In the brain sections, the virus-infected cells cytologically had the appearance of neurons and microglial cells. The viral load, defined by the percentage of cells infected in a given field, was very high in the lung, spleen, and brain. Viral infection was associated with a marked increase in the number of cells expressing tumor necrosis factor alpha and concomitant reduction in the cells expressing suppressors of cytokine signaling (SOCS). It is concluded that measles infection should be in the differential diagnosis of a rapidly progressive illness in young children in the United States and that the pathogenesis is based, in part, on massive viral infection with up-regulation of cytokine expression that likely reflects, in part, down-regulation of inhibitors of cytokine mRNA receptor synthesis.