Rotaviral infection is a common cause of gastroenteritis and pharyngitis; to our knowledge, infection has not been associated with severe pneumonia. We report on two cases of fatal pneumonitis in 49-and 54-year-old men; the latter was on long-term steroid treatment of multiple sclerosis. In the latter case, the histologic examination after a several week history of symptoms showed severe organizing interstitital pneumonitis and necrotizing bronchiolitis with extensive squamous metaplasia. The other case, which was fatal several days after the onset of symptoms, showed marked septal capillaritis with denudement of the alveolar pneumocytes, extravascated red blood cells, and intravascular thrombi formation. In each case, rotaviral RNA was localized by reverse transcription (RT) in situ PCR to the endothelial cells of the alveolar capillaries, macrophages, and pneumocytes as well as, in the second case, to the squamous metaplastic cells. Immunohistochemical analysis for the virus demonstrated an equivalent histologic distribution. It is concluded that rotaviral infection can lead to fatal pneumonitis and that the mechanism of this complication is centered on a diffuse septal endothelialitis with concomitant tissue damage.