Fifty-nine patients who survived more than 30 days after lung transplantation (52 heart-lung, seven double lung, and two single lung) were studied for mortality and morbidity related to cytomegalovirus (CMV) infection. CMV infection developed in 32 patients (54%) and was more common in the preoperatively CMV seropositive group (95%) as compared with the seronegative group (38%). Symptomatic infections, pneumonitis, and CMV-related mortality, however, were higher in the seronegative (primary infection) group and actuarial survival was worse in these patients (40% and 23% at 1 and 5 years, respectively). Transplantation of CMV-seropositive donor organs was associated with a significantly higher incidence of primary infection and use of seronegative blood products led to a decrease in the primary CMV infection rate. The mortality of primary CMV infection was 54% and this was associated with a significantly higher rate of pulmonary superinfections in the first year after transplantation. The incidence of late pulmonary infections was associated with the development of chronic rejection rather than CMV status. We conclude that primary CMV infection has a major impact on the outcome after lung transplantation. The high mortality of primary infections justifies an aggressive approach to prevention and treatment in the at-risk seronegative group.