OBJECTIVES: Valganciclovir (VGV) is an antiviral agent used as prophylaxis of cytomegalovirus (CMV) infection following solid organ transplant.  Limited studies regarding CMV prophylaxis with VGV in liver transplant recipients (LTR) have been performed.  This study is a cost effectiveness analysis of VGV prevention strategies in LTR from a payer perspective. METHODS: We evaluated the cost of preventing hospitalization due to CMV in LTR at moderate to high risk of CMV.  A decision tree model was constructed using TreeAge 2013.  Data source for effectiveness was used from the results of our single-center retrospective analysis and cost data were from previously published data and the RedBook®.   The model included costs of CMV prophylaxis, rates of CMV viremia, costs of outpatient treatment, and rates of inpatient admission due to CMV.   We compared two protocols, one using lower doses and shorter duration of VGV prophylaxis (Group A) to a more recent protocol utilizing both higher doses and longer duration of VGV prophylaxis (Group B).  Costs expressed in 2013 US dollars. RESULTS: Costs associated with prophylaxis in group A were lower, despite a higher percentage of patients requiring treatment.  Cost per-patient for prophylaxis in group A was $8,535.42 versus $14,926.73 in group B.  In patients with CMV infection, 50% required hospitalization regardless of VGV prophylaxis group.   Thus, 10% of patients in group A were hospitalized for treatment of CMV infection and only 4% of patients in group B required hospitalization.  An ICER demonstrated that the prevention of one inpatient hospitalization due to CMV would cost $106,521.83. A one-way sensitivity analysis varying cost of VGV based on previously published costs demonstrated that the ICER for group B varies from $70,316 to $131,902. CONCLUSIONS: While the increased dose and duration of VGV is effective at preventing CMV infection and hospitalization, it is associated with a large incremental cost.