Although cytomegalovirus (CMV) infections are common throughout the world, little is known about the means of person-to-person transmission. To determine whether infection could be established by a respiratory route, studies were conducted in a murine CMV (MCMV) model by using intranasal inoculation. The infectious dose which resulted in pulmonary and systemic infection of half the mice was 100 plaque-forming units of MCMV. Here, infection was subclinical, but virus replicated in the lungs and subsequently disseminated via the blood to other organs within 7 days. The serum immunofluorescence antibody titer peaked by day 21. None of these mice died, although focal peribronchial interstitial pneumonitis was found in infected animals. In mice given greater than or equal to 10(4) plaque-forming units of MCMV intranasally, severe diffuse interstitial pneumonitis resulted uniformly, closely resembling that seen in immunocompromised patients and in newborn infants, and 20% of the animals died. Normal pulmonary architecture was obliterated by sheets of histiocytes, many containing MCMV intranuclear inclusions, and by accumulation of proteinaceous fluid in the interstitial and alveolar spaces. Of relevance to human disease, these experiments show that MCMV as a sole pathogen can cause severe interstitial pneumonitis in normal mice and that subclinical systemic infection results from respiratory inoculation of small amounts of virus.