Background. Gut decontamination could have some benefits in preventing infectious complications in acute pancreatitis (AP).Objectives. To investigate whether the administration of rifaximin could have an impact on the outcomes of AP. Materials and methods.We conducted a retrospective study on 373 patients with a median age of 50 years that were admitted to our Department of Gastroenterology in the years 2001-2016 with a diagnosis of AP. Patients were subclassified according to the revised Atlanta criteria: mild acute pancreatitis (MAP), moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP). Thereafter, all the patients were divided into 2 groups: in the 1 st group (R0) with MSAP and SAP, patients did not receive rifaximin, and in the 2 nd group (R1), in the cases of MSAP and SAP, rifaximin was administered to patients at a dose of 3 × 400 mg (for at least 5 days and up to 7 days). There was no other difference in the treatment between the groups. The median duration of hospital stay, the number of infectious complications and the mortality rate were recorded for both groups.Results. A significant difference was observed between median durations of hospitalization between the groups with (R1) and without (R0) rifaximin treatment (14 days compared to 24 days, p = 0.001) and in the number of patients infected with pancreatic necrosis (7 compared to 1, p = 0.0487). However, there was no statistically significant difference between the R1 and R0 group in terms of mortality rate. Conclusions.The results indicate that rifaximin seems to be a promising novel therapeutic option in MSAP and SAP.