Because cytomegalovirus (CMV) can be isolated from pulmonary secretions of human immunodeficiency virus (HIV)-infected patients without causing disease, its clinical significance as a cause of pneumonia in this patient population is frequently questioned. In a 22-month period, CMV pneumonia was diagnosed in 17 (8%) of 210 HIV-infected patients who underwent lung biopsy on the basis of microbiological and histologic criteria. The clinical presentations of these patients were nonspecific, including fever (100% of patients), shortness of breath (71%), cough (76%), and Pao2 of < 75 mm Hg (88%). A high correlation in the degree of viral burden in lung biopsy specimens was demonstrated by histologic examination, immunohistochemical analysis, and in situ hybridization. No other pulmonary pathogens were identified for nine patients, whereas other possible causes of pneumonia were present in eight: 11 patients had evidence of extrapulmonary CMV disease at presentation. Most patients initially responded to specific anti-CMV therapy; the overall mean survival +/- SD was 3.1 +/- 2.5 months. CMV should be considered as a possible cause of pneumonia in patients with advanced AIDS especially if CMV infection is documented at other sites.