Background. Hepatic encephalopathy (HE) is a frequent and debilitating complication of liver disease. Treatments include lactulose and rifaximin-α. The objective of this literature review and meta-analysis was to assess the overall cost-effectiveness of rifaximin-α in HE treatment. Methods. Electronic database searches were conducted in November 2020 to identify cost-effectiveness studies comparing rifaximin-α with other interventions in HE, published in English. Incremental net benefit (INB) was calculated for each study using difference in effectiveness, difference in costs, and the willingness-to-pay threshold, or gross domestic product per capita for each country, and 95% confidence intervals (CI) were constructed. Costs were standardised to 2019 US$. An intervention was considered cost-effective if the INB was positive. Meta-analysis was used to pool calculated INB across studies, using a fixed-effects model if there was no heterogeneity or a random-effects model. Results. Eleven studies were included in the meta-analysis. For rifaximin-α plus lactulose in the second-line setting, the pooled INB was estimated at $20,156 (95% CI: $13,593-$29,887) versus lactulose monotherapy. For rifaximin-α monotherapy in the first-line setting, the pooled INB was $4834 (95% CI: $1601-$14,596) versus lactulose monotherapy. Due to lack of available data, meta-analyses were not possible for rifaximin-α added to lactulose therapy versus lactulose monotherapy in the first-line setting or for rifaximin-α as salvage therapy in the second-line setting. Conclusions. Rifaximin-α as an add-on treatment to lactulose in the second-line setting or as monotherapy in the first-line setting would be a cost-effective treatment for HE compared with lactulose monotherapy.