ABSTRACT Background: Hepatorenal syndrome type II and acute kidney injury found in 20% of cirrhotic patients. Rifaximin was found to reduce the frequency of hepatorenal syndrome type II and acute kidney injury in alcohol cirrhotic patients. This study aimed to evaluate the efficacy of rifaximin in prevention of hepatorenal syndrome type II and acute kidney injury in Egyptian HCV cirrhotic patients. Methods: The study included 120 patients with decompensated post HCV cirrhosis selected from patients admitted to Tropical Medicine department and intensive care unit and from patients admitted to Internal Medicine department and intensive care unit. They were classified into two groups the first was a control group (n = 60) and the second was the rifaximin group (n = 60). Rifaximin group patients were administered rifaximin tablet 550 mg twice daily for 12 weeks. All patients were revaluated every 4 weeks and followed up for 12 weeks in Tropical Medicine outpatient clinic and Internal Medicine outpatient clinic. Results: The incidence rate ratio of acute kidney injury (IRR 0.7 [95 % CI 0.53-0.92]) and hepatorenal syndrome type II (IRR 0.21 [95 % CI 0.06–0.70]) was statistically lower in the rifaximin group than the control group. The estimated mean change in the control group was higher than the rifaximin group in blood urea nitrogen [18.93(17.34-20.52) vs. 16.145(13.09-19.2) mg/dl; P= 0.029] and serum creatinine [1.0525(0.9425-1.1625) vs. 0.995(0.885-1.105) mg/dl; P= 0.038]. Conclusion: Use of rifaximin is associated with decreased incidence of hepatorenal syndrome type II and acute kidney injury in Egyptian HCV cirrhotic patients. Keywords: Rifaximin, hepatorenal syndrome type II, acute kidney injury, cirrhosis.