Purpose Cytomegalovirus (CMV) infection increases morbidity and mortality in lung transplant recipients. Our center identified CMV-resistant (rCMV) disease resulting in the death of 3 out of 4 cases. We attributed rCMV to erratic dosing, inconsistent medication levels, and a shortened duration of valganciclovir (Val) prophylaxis. We describe the effect of changes in a prophylaxis protocol in order to prevent rCMV in at-risk patients. Methods and Materials The Pre-intervention cohort (Pre 3/08-4/11) received prophylaxis with Val for 3 (D+ and D-/R+) to 6 (D+/R-) months; Val was held for WBC <4. The post-intervention cohort (Post, 11/10-9/11) had IV ganciclovir (Gan) induction for 2 weeks followed by Val for 6 months (D+/R- also received CMV-IVIg (150 mg/kg for 6 doses). Val was continued through leukopenia & IS was adjusted instead. A calcineurin inhibitor, anti-proliferative agent, and prednisone were used for primary immunosuppression (IS). Patients surviving >6 months and followed ≥12 months were included. Frequency of CMV events, time to first event (unadjusted and adjusted for changes in Val or IS), frequency of changes in Val dosing or IS (due to adverse effects) and frequency of rCMV were compared. Results 54 Pre and 23 Post patients were included. CMV event frequency (Pre 23/54 (43%) vs. Post 9/23 (39%) (p=0.77)), median time to events (Pre 54 days, Post 69 days) and time to event analysis was not different between groups (HR 1.087, 95% CI 0.50-2.35). Changes in IS or Val dosing were not more frequent Pre (11/54 (20%)) versus Post (6/23 (26%)) (p=0.57). Pre was associated with development of rCMV in 4/54 (7%) patients, but rCMV in Post has not yet been detected. Conclusions Our combination therapy was successful in preventing rCMV in at-risk patients even though the frequency of CMV events and the changes in IS or Val dosing were unchanged. Our findings suggest that a longer duration of prophylaxis with consistent dosing and perhaps the addition of CMV-IVIg leads to a reduction in rCMV.