OBJECTIVES: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs most often in a context of acute or chronic liver disease. Despite the seriousness of the pathology, only a few treatments have been developed for improving its management. Rifaximin-α is the first treatment that has been clinically developed for overt HE (OHE) episodes. Recent results of clinical studies demonstrated its significant improvement in the health-related quality of life. The objective of the current study was to estimate the long-term cost-effectiveness of rifaximin-α used in combination with lactulose compared to lactulose monotherapy in cirrhotic patients, who have experienced at least two prior OHE events. METHODS:  A Markov model was used to determine whether rifaximin-α is a cost-effective therapy for the prevention of OHE taking a collectve perspective as recommended by French health technology assessment guidelines. Costs were based on current French treatment practices. The transition between health states was based on the analysis of the rifaximin-α pivotal clinical trials RFHE3001 and RFHE3002. The main outcome of the model was the cost per quality adjusted life years (QALY). The robustness of the model was studied using the one-way and the probabilistic sensitivity analysis. RESULTS:  The results indicate that rifaximin-α is a cost-effective treatment option with an incremental cost per QALY gained of €19 187 and €18 517 over two different time horizons (2 and 5 years). The results of the Monte Carlo simulations showed that the average ICER is equal to €13 507 (CI: [€8 887 – €21 733]). The analysis indicates a 99.8% probability that the ICER would be less than €27 000/QALY. CONCLUSIONS:  For the societal willingness to pay threshold of €27 000 per QALY gained, rifaximin-α in combination with lactulose is a cost-effective and affordable treatment for patients who have experienced at least two prior overt HE episodes.