Background/Objectives: Rifaximin is commonly used for patients with hepatic encephalopathy (HE); however, there is little data on the effects of its long-term (>1 year) administration in Jap-anese patients with cirrhosis. Therefore, we examined the effects and safety of three-year rifaxi-min treatment on HE in Japan. Methods: A total of 190 patients with cirrhosis who were contin-uously administered rifaximin for more than one year developed overt or covert HE, which was diagnosed by a physician. Laboratory data were collected at baseline, 3, 6, 12, 18, 24, 30, and 36 months following rifaximin administration. We examined the cumulative OHE incidences, overall survival rates, and hepatic functional reserves following rifaximin treatment. The occur-rence of adverse events was also assessed. Results: Ammonia levels improved significantly after 3 months of rifaximin administration, which continued for three years. Serum albumin and pro-thrombin activity also significantly improved after three years of rifaximin administration. Cumulative overt HE incidences were 12.1%, 19.7%, and 24.9% at 1, 2, and 3 years, respectively. The survival rates following rifaximin treatment were 100%, 88.9%, and 77.8% at 1, 2, and 3 years, respectively. In contrast, renal function and electrolytes did not change following rifaximin ad-ministration. Only three (1.6%) patients discontinued RFX therapy because of severe diarrhea after a year of RFX administration. No other serious adverse events were observed. Conclusion: Long-term rifaximin treatment (three years) is effective and safe for patients with HE and im-proves the hepatic function reserve and overall survival.