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 ...