Virus replication and interstitial pneumonia were studied in BALB/c mice inoculated intranasally with murine cytomegalovirus (MCMV). In normal mice MCMV replicated in lung tissue but did not produce any consistent histologic abnormalities through day 21. The addition of a single dose of cyclophosphamide (0.20 mg/g) 24 hr after virus inoculation resulted in a slight increase in lung virus titers on day 10. No histologic abnormalities were noted before day 10. However, 22 or 32 virus-infected mice treated with a single dose of cyclophosphamide but only two of 26 simultaneously mock-infected, cyclophosphamide-treated mice developed severe interstitial pneumonia 10-14 days after inoculation. In contrast, animals given cyclophosphamide (0.05 mg/g) every five days after the initial dose developed a 10-fold increase in lung virus titer, but interstitial pneumonia was not observed. These data suggest that the interstitial pneumonitis seen with MCMV pulmonary infection may be immunologically mediated rather than the result of direct viral damage to the lung.