Background: Cytomegalovirus (CMV) infection remains a serious problem after lung transplantation. The purpose of this study was to evaluate the efficacy of CytoGam, a CMV hyperimmune globulin (CMV-IGIV), as CMV prophylaxis after lung transplantation. Methods: This prospective, randomized, open-label study compared prophylaxis with CMV-IGIV and no prophylaxis in 44 CMV-seropositive lung transplant recipients. The primary end-point was development of CMV viremia during the first year after transplantation. Results: Cytomegalovirus viremia was detected in 13 of 22 recipients without prophylaxis and in 16 of 22 recipients with CMV-IGIV prophylaxis (p = 0.19). Cytomegalovirus pneumonitis developed in 8 controls vs in 11 CMV-IGIV recipients (p = 0.54). We found no significant difference between the groups in the incidence of positive shell vial assays (6.8% ± 6.5% without vs 11.2% ± 10.1% with prophylaxis, p = 0.09) or in the attack rate of CMV pneumonitis (0.41 ± 0.59 episodes/patient without vs 0.86 ± 0.99 episodes/patient with prophylaxis, p = 0.07). Similarly, no difference was apparent in the time to onset of CMV viremia, to detection of CMV DNA in peripheral blood leukocytes by polymerase chain reaction, or to development of CMV pneumonitis. The incidence of acute rejection and bronchiolitis obliterans syndrome and the survival rate during the first post-transplant year did not differ between the groups. Conclusions: Prophylaxis with CMV-IGIV alone did not decrease CMV viremia or pneumonitis, did not decrease the incidence of acute rejection or bronchiolitis obliterans syndrome, and did not affect 1-year survival of CMV-seropositive lung transplant recipients at our center.