Among solid-organ recipients, those with lung transplants are at highest risk of cytomegalovirus (CMV) infection or to die of CMV-associated disease. We evaluated the effect of combined CMV antiviral prophylaxis and CMV-immunoglobulin prophylaxis on CMV-associated pneumonia diagnosed in 303 follow-up transbronchial biopsy (TBB) specimens from lung transplant recipients. At our center, 24 recipients (control group; 1999-2002) received acyclovir for 24 months and 33 recipients (study group; 2003-2008) received combined CMV prophylaxis consisting of CMV immunoglobulin on days 1, 4, 8, 15, and 30 and monthly for 12 months plus gancyclovir or valgancyclovir from postoperative day 21 for 3 weeks followed by acyclovir for up to 24 months. The percentage of pneumonia-positive TBB specimens at 1-month follow-up was similar in the study and control groups: 9.1% (3 of 33 specimens) vs 8.3% (2 of 24) (P = .90). However, after the first month, the percentage of pneumonia-positive TBB specimens was significantly lower in the study group in the first year (months 3, 6, 9, and 12) of follow-up, at 1% (1 of 99) vs 6.4% (5 of 78) (P = .048), and in the first 2 years (months 3, 6, 9, 12, 18, and 24), at 0.8% (1 of 122) vs 6.5% (8 of 124) (P = .02). These data suggest the efficacy of combined prophylaxis to decrease the incidence of CMV-associated pneumonia after the first month in lung transplant recipients. The effect of combined prophylaxis after transplantation seems useful to prevent CMV-associated pneumonia not only in the first year after lung transplantation but also in the second year, which suggests a long-lasting immunologic role of prophylaxis.