Background and study aims: Advanced liver disease frequently culminates in hepatic encephalopathy (HE), which can be classified as covert or overt HE, with subtle or clinically obvious changes respectively. 30-40% of patients with cirrhosis develop overt HE, which negatively affects the patients’ quality of life. Next to lactulose, rifaximin-a has been prescribed as a second line therapy to treat and reduce the risk of recurrence of overt HE. In this study, we aimed to evaluate the effect of rifaximin-a therapy, both on the number of occurring infections and on the evolution in hospital admissions of patients with overt HE. Patients and methods: A total of 66 cirrhotic patients, treated for at least 6 months with rifaximin-a at AZ Maria Middelares, between October 1st 2014 and January 1st 2020, were included in the study analysis. Medical records of all patients were evaluated over a period of 6 months prior and after initiation of rifaximin-a therapy. Results: Data analysis revealed that the included cirrhotic patients were severely ill, with a mean model for end-stage liver disease (MELD) score of 21, and a median Child Pugh score of 11. Among these patients, rifaximin-a treatment significantly downgraded the total number of infections, with a main effect on respiratory infections. Furthermore, rifaximin-a therapy led to a significant decrease in HE-related, as well as in other liver-related hospital admissions. Conclusions: This study confirms the potential value of rifaximin-a in reducing the number of developing infections and hospital admissions in a severely ill cirrhotic patient population.