A total of 166 consecutive clinical episodes of pneumonitis in patients with acquired immune deficiency syndrome (AIDS) (1) or antibody positive for human immune deficiency virus (HIV) were investigated for evidence of cytomegalovirus (CMV) infection in their lungs and at peripheral sites to determine the pathogenicity of this virus in the lung and its relationship to peripheral CMV shedding. Evidence of CMV infection was sought in bronchoalveolar lavage (BAL) fluid, blood, saliva, and urine using a specific monoclonal antibody to antigens produced by CMV-infected cells within 24 h. Although CMV was detected in 31 (19%) of BAL fluid specimens, in only six episodes was this the sole pathologic finding. In the remaining episodes either another infectious agent, Kaposi's sarcoma, or lymphoid interstitial pneumonitis was found or no pathogen was detected. None of the patients were given specific anti-CMV treatment, and all but two recovered, including those patients in whom CMV was the sole finding at BAL. The presence of peripheral shedding of CMV did not have any significance in mortality or morbidity. Our findings are in direct contrast to those in recipients of allogeneic bone marrow transplants, in whom CMV pneumonitis is associated with a high mortality. We postulate that this difference is because AIDS patients cannot mount the destructive immune response to CMV in the lung, which we believe to be the basis of the pathology seen in the former group. WE conclude that CMV is not a pathogen in the lungs of patients with HIV infection, and we suggest that its presence at this site does not warrant specific therapy in these patients. However, if current or future therapies for HIV restore the immune capabilities of AIDS patients, we predict that life-threatening CMV pneumonitis may develop.