Minimal hepatic encephalopathy (MHE) occurs in up to 70% of patients with cirrhosis and has a clear impact on health-related quality of life (HRQOL) in these patients. Antibiotics leading to reductions in circulating ammonia have been used in the past for the treatment of MHE. However, serious adverse effects such as nephrotoxicity, ototoxicity, and peripheral neuropathy limit their use to relatively short time periods. In this issue of the American Journal of Gastroenterology, an article by Sidhu et al. demonstrates unequivocally that the antibiotic rifaximin, a minimally absorbed antibiotic with broad spectrum activity, improves psychometric test performance scores and concomitantly improves HRQOL in patients with MHE (the RIME Trial). Rifaximin was well tolerated. Results of the RIME Trial represent an important step in the establishment of this antibiotic as an effective and safe treatment for MHE.