Rifaximin-α as an adjunct to lactulose is reimbursed in the Netherlands for prevention of the third and subsequent episodes of overt Hepatic Encephalopathy (HE) in cirrhotic patients. However, use of rifaximin-α remains limited. This study evaluates the clinical and economic impact of treating all patients eligible under Dutch reimbursement conditions with rifaximin-α as an adjunct to lactulose for the prevention of overt HE in the Netherlands from a hospital and healthcare payer’s perspective. A budget impact analysis was performed following national and international guidelines. Resource use was based on Dutch real-world data. HE-related cost inputs were based on the declaration codes, Dutch cost manual, and actual drug list prices. Several sensitivity and scenario analyses were conducted to assess model robustness. Treating eligible HE patients with rifaximin-α in addition to lactulose saves €4,487 and costs €249 per patient over a 5-year period compared with lactulose monotherapy from hospital and healthcare payer’s perspectives, respectively. In the Netherlands, an estimated 38% of the 2,567 eligible patients are currently being treated with rifaximin-α. Optimizing rifaximin-α use by treating all eligible patients with the rifaximin-α + lactulose could save more than 3,000 hospital admissions, almost 15,000 hospital bed days, and 300 deaths over a 5-year period. Despite increased drug costs, treatment is estimated to result in potential cost savings over a 5-year period of 7.2 million euros from a Dutch hospital perspective. The budget impact is 397,770 euros from a healthcare payer’s perspective. Next to a clinical perspective, also from an economic perspective, wider prescription of rifaximin-α adhering to guidelines could be beneficial to reduce costs from a hospital perspective. From a healthcare payer’s perspective, costs increase with addition of rifaximin-α due to relative better survival causing relatively higher drug and liver transplantation-related costs.