OBJECTIVES Prolonged exposure to CNI-based immunosuppressant therapy (IS) in liver transplant (LTx) recipients is associated with long-term complications. In the global registration trial H2304, patients receiving everolimus + reduced tacrolimus (EVR + reduced TAC) demonstrated non-inferior efficacy and superior renal function at Month 12 that was sustained at 36 months compared to tacrolimus alone (TAC). A peer-reviewed Markov model has been adapted to the Italian setting to explore the  cost-effectiveness of EVR + reduced TAC compared to TAC, in de novo liver-recipients. METHODS The model estimates long-term outcomes associated with IS following LTx along two independent pathways: 1. liver-related (acute rejection, hepatocellular carcinoma, hepatitis C [HCV] recurrence, graft loss); 2. kidney-related (chronic kidney disease, dialysis, renal transplantation) and death. All patients, stratified by liver diagnosis, entered the model at time of LTx and followed both pathways, allowing for multiple combinations of liver and kidney health states.The lifetime model used an annual cycle length except for the 1^styear post LTx (quarterly). Efficacy and safety of IS strategies were assessed through the risk of acute rejection, change in renal function, HCV fibrosis progression and frequency of adverse events. Utilities and costs were assigned to each renal and liver state. Subgroup and sensitivity analyses were performed. RESULTS With a mean life expectancy of 18 years, the model predicts patients treated with EVR + reduced TAC gain on average 1.84 years of life and 1.55 QALYs vs. TAC. The risk of acute rejection was reduced by 20%. The incremental cost of EVR + TAC was €38,884 per life year gained and €46,103 per QALY gained vs. TAC. CONCLUSIONS This model shows a strategy of EVR + reduced TAC post- LTx improves survival and quality of life. Higher treatment costs are offset by slower progression of renal deterioration predicted in the first 10 years and fewer lifetime liver complications.