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Background: Hepatitis E can potentially progress to HEV-related acute liver failure (HEV-ALF). East and South Asia bear a substantial burden of HEV infection, with Bangladesh, China, and India facing the most severe threat in this region. Therefore, we conducted a systematic review and meta-analysis to evaluate the burden of HEV-ALF in these three high-risk countries. Methods: A systematic literature search was performed utilizing PubMed, the Cochrane Library, Medline, Embase, and Web of Science databases. Studies in English or Chinese that reported data on the burden of HEV-ALF in Bangladesh, China and India were included. Outcomes were pooled with meta-analysis utilizing R software. Estimates were calculated with random-effects models, and subgroup analysis and sensitivity analysis were conducted to address heterogeneity. Egger's test and Begg's test were performed to assess publication bias. Results: A total of 20 eligible studies were included in this study. The pooled HEV-attributable proportion of viral-related acute liver failure was estimated to be 40.0% (95% CI: 0.28–0.52), 30.0% (95% CI: 0.18–0.44), and 61.0% (95% CI: 0.49–0.72) among non-pregnant individuals in India, China and Bangladesh, while in Indian pregnant females, it was 71.0% (95% CI: 0.62–0.79). The combined prevalence among non-pregnant HEV-infected participants was 28.0% (95% CI: 0.20–0.37) and 10.0% (95% CI: 0.01–0.28) in India and China, and it was 34.0% (95% CI: 0.27–0.42) in Indian pregnant females with HEV infection. The overall mortality of HEV-ALF was estimated to be 32.0% (95% CI: 0.23–0.42) and 64.0% (95% CI: 0.50–0.77) among the non-pregnant and the pregnant participants in India, and it was 23.0% (95% CI: 0.14–0.34) in Chinese non-pregnant participants. Conclusions: The burden of HEV-ALF in Bangladesh, China, and India is non-negligible despite geographic and population heterogeneity. The prevention of HEV infection and early recognition of HEV-ALF are of great significance, especially in high-risk countries and populations. Registration: PROSPERO registration ID is CRD42022382101. [ABSTRACT FROM AUTHOR]