Using aggressive surveillance of blood, bronchoalveolar lavage (BAL) fluid, and lung tissue, we sought to determine the incidence of cytomegalovirus (CMV) pneumonitis in isolated lung transplant recipients and to characterize its impact on pulmonary function, chronic rejection, and survival. Forty-six lung transplant recipients who survived greater than 30 days had prospective documentation of CMV infection in blood and BAL fluid and regular surveillance with transbronchial lung biopsy. CMV infection was documented in 92% of patients who were D-/R+, D+/R+, or D+/R-, and the incidence of histologically confirmed CMV pneumonitis among these patients was 75%. No D-/R- patient experienced CMV infection or disease. D+/R- patients experienced more frequent and severe episodes, and ganciclovir prophylaxis during the first 2 wk was not useful. CMV pneumonitis was accompanied by detectable radiographic changes in less than one third of cases. The detection of CMV in BAL fluid was not predictive of CMV pneumonitis on biopsy, except in D+/R- patients during the first 90 days after transplantation. There was no evidence of an adverse impact because of CMV infection on pulmonary function during the first year after transplantation. A relationship between CMV infection and bronchiolitis obliterans could not be documented; however, D+/R- patients had higher morbidity and a trend toward lower survival. In a multivariate analysis, D+/R- status was an independent predictor of death.