OBJECTIVES: Hepatic encephalopathy (HE) is a serious complication of liver disease. HE presents as a spectrum of neurocognitive impairments, from mild HE to coma. Direct measurement, or derivation of utility values related to treatment using a generic QoL mapping procedure may not provide the most valid measures, given the nature of the condition. Rifaximin-α is a treatment for HE that has been shown to reduce the recurrence of HE and HE-related hospitalisation. Following an exercise using a disease specific instrument that yielded a utility difference of 0.155 units, here we attempted to indirectly estimate the utility impact of Rifaximin-α in patients with HE. METHODS: Data from a six month, phase-3 RCT of rifaximin-α in HE patients was used. In this study, monthly PROs including SF-36 were recorded until an HE event had occurred or until the end of study. We estimated the EQ-5D index (estEQ-5Dindex) using a recognised SF-12 mapping procedure. Due to missing observations and differences in baseline utility, linear interpolation of utility values was applied, and the individual changes from baseline in the estEQ-5Dindex were characterised. RESULTS: At baseline, the estEQ-5Dindex was 0.563 units (SD 0.263) units in the rifaximin-α arm, and 0.587 (0.211) in the placebo arm (p=0.368). There was no discernible difference using mean values throughout (overall mean estEQ-5Dindex at end of study 0.643 (0.23) for rifaximin-α vs. 0.647 (0.24; p=0.922)). The overall percentage of missing data was 20% of subjects and 14% of potential observations. The mean difference from end of study to baseline in utility was 0.018 units (SEM 0.02 for rifaximin-α vs. -0.013 for placebo (0.031; p=0.171). CONCLUSIONS: Even with an insensitive methodology using generic quality of life we demonstrated that rifaximin-α was associated with a discernible, clinically meaningful change in utility in cognitively impaired patients. In these patients, direct measurement of utility using a PRO was inappropriate.