Rifaximin (Xifaxan, Salix) is a broad-spectrum oral antibiotic that is gut-selective and minimally absorbed. The agent has demonstrated efficacy in acute hepatic encephalopathy (HE). The randomized, double-blind, multinational, phase III trial RFHE3001, conducted in 299 patients with cirrhosis and a history of recurrent overt episodic HE, showed that rifaximin reduces the risk of breakthrough overt HE by 58% compared to placebo. In the current analysis, Sanyal and colleagues evaluated the effects of rifaximin and breakthrough HE on patient-reported health-related quality of life in patients enrolled in RFHE3001. Quality of life was assessed using the validated and disease-specific Chronic Liver Disease Questionnaire (CLDQ), in which 6 domains are ranked on a 7-point scale, with higher scores indicating a better quality of life. The investigators found that rifaximin was associated with a significant improvement in the mean time-weighted average (TWA) score for the overall CLDQ (3.7 vs 2.9; P=.0093) and for all individual domains, including fatigue (3.2 vs 2.5; P=.0087). Adverse events occurred in 80% of patients in each arm. The most common adverse events were peripheral edema (15.0% with rifaximin vs 8.2% with placebo), nausea (14.3% vs 13.2%), dizziness (12.9% vs 8.2%), fatigue (12.1% vs 11.3%), and diarrhea (10.7% vs 13.2%). Twenty patients died during the trial, including 9 patients receiving rifaximin and 11 patients receiving placebo. The majority of deaths were attributed to disease progression. The investigators concluded that rifaximin is associated with significant quality-of-life improvements in patients with hepatic cirrhosis and recurrent, overt HE.