Abstract: This retrospective review compared oral valganciclovir (VGCV) 450 mg daily for 6 months versus oral ganciclovir (GCV) 1000 mg 3 times daily for 3 months in preventing cytomegalovirus (CMV) disease in high-risk liver transplant recipients. We evaluated all CMV donor positive–recipient negative liver transplant recipients managed at University Health System in San Antonio, Texas from August 1996 to September 2006. CMV disease was confirmed by polymerase chain-reaction or antigenemia assay, and CMV invasive disease by tissue biopsy. Patient demographics, laboratory results, complications, and therapies were collected via retrospective chart review. Patients <18 years of age or those who died during transplant admission were excluded. Primary endpoints included incidence, onset, and severity of CMV disease up to 1 year post transplant. Data collection also included patient demographics, immunosuppression, CMV treatment regimens, and relevant lab results. A total of 64 patients (43 VGCV and 21 GCV) were identified. Four patients developed CMV disease: VGCV (3/43, 7%) versus GCV (1/21, 5%) (P=1.0), with 1 VGCV patient experiencing tissue-invasive CMV. In all cases, onset of CMV disease occurred after prophylaxis was discontinued. Onset occurred at 24, 27, and 45 weeks post transplant in the VGCV group, and at 26 weeks in the 1 patient on GCV. Four patients received rabbit anti-thymocyte globulin (rATG) induction; 1 patient received rATG and developed CMV disease, with no statistical difference compared with the 3 remaining patients who received rATG but did not develop CMV disease (P=0.09). No difference was found in incidence of CMV disease between patients who received GCV and those who received VGCV at our institution.