In five spontaneous outbreaks, sixty-four BALB/cByJ mice developed Reye's-like syndrome 4 to 33 days after introduction into mouse rooms known to harbor a variety of indigenous murine viruses. The clinical course lasted 24 hours and consisted of progressively deteriorating consciousness and hyperventilation, usually leading to death. Mice killed and necropsied while stuporous or comatose had serum ammonia levels of 2524 +/- 179 versus 66 +/- 8 micrograms/dl for control BALB/cByJ mice. Necropsy findings included swollen, diffusely pale yellow livers with panlobular microvesicular fatty change, pale renal cortices with epithelial fat droplets of the proximal convoluted tubules, and Alzheimer type II astrocytosis of the neocortex, corpus striatum, hippocampus, and thalamus. In three of the five outbreaks involving 66% of affected animals, mice had active coronaviral enteritis. Electron microscopic changes in hepatocytes, neocortical astrocytes, and neurons were similar to or identical with those described for the acute phase of Reye's syndrome in man. The epizootiology of these outbreaks and the apparent synchrony between Reye's syndrome-like illness and the stage of intestinal coronavirus infections in some of these outbreaks suggest that one or more naturally occurring murine viruses were of etiologic significance.