OBJECTIVES: Each year, approximately 110,000 hospitalizations for hepatic encephalopathy (HE) occur, totaling almost $1 billion U.S. in health care expenses. Our purpose was to determine if there was a difference in the recurrence of overt HE in the six months following an initial HE event between patients who received preventative therapy with lactulose versus lactulose and rifaximin. METHODS: This was a retrospective cohort study that used a 10% random sample of medical and pharmacy claims obtained from the IMS LifeLink PharMetrics Plus database for the study period January 1, 2006 through June 30, 2015. Descriptive analyses were conducted to compare demographic and clinical characteristics between patients who received lactulose or lactulose and rifaximin. Kaplan-Meier curves and a Cox proportional hazard model, adjusting for concomitant medications, comorbidities, and diagnoses related to liver disease were estimated. RESULTS: Among patients in the lactulose and rifaximin group (n=169) and the lactulose group (n=437), there was no significant difference in the average age (56.9 vs. 56.0; p=0.792) or Charlson comorbidity index (6 vs. 6; p=0.246). A significantly greater proportion of patients in the lactulose and rifaximin group were on spironolactone (73.4% vs. 61.8%, p=0.007), a proton pump inhibitor (73.4% vs. 61.8%, p=0.007), and ursodiol (16.6% vs. 8.0%; p=0.002). There was no difference in hospitalization for HE between groups (16.0% vs. 15.3%; p=0.841). After adjusting for potential confounders, there was no significant difference in risk for an event between groups (hazard ratio=1.045; 95% confidence interval 0.806-1.28). CONCLUSIONS: The addition of rifaximin to lactulose did not alter the proportion of patients who experienced their second overt HE event. This finding differs from previously reported results and may be the result of residual, unobserved confounding.