OBJECTIVES: Hepatitis E virus (HEV) is a global health concern that causes acute hepatitis with severe consequences, particularly in patients with chronic liver disease. Despite the availability of a recombinant hepatitis E vaccine (Hecolin), its safety and immunogenicity in patients with pre-existing liver cirrhosis remain uncertain. This study aimed to assess the safety and immunogenicity of Hecolin in individuals with compensated liver cirrhosis who have chronic hepatitis B (CHB). METHODS: This study was conducted in Shenzhen City, China, from November 2019 to June 2022. The adult participants were stratified into untreated CHB, CHB treatment, CHB cirrhosis, and control groups based on their disease status. Safety assessment included adverse events and liver function tests. Serological samples were collected before vaccination and 1 month after both the first and third dose of vaccination to assess anti-HEV IgG antibodies. RESULTS: A total of 162 eligible participants, including 43 with CHB cirrhosis, 50 with treated CHB, 50 with untreated CHB and 19 controls were included in the study. A total of 157 (96.9%) participants received three doses of the vaccine. Safety analysis revealed 7-day local adverse events in 14.0%, 24.0%, 12.0%, and 5.26% and systemic adverse events in 6.98%, 12.0%, 4.0%, and 0% across the cirrhosis, treated, untreated, and control groups, respectively. No serious adverse events were deemed to be causally related to vaccination. In the per-protocol set for immunogenicity, all vaccinated participants with cirrhosis (95% confidence intervals: 88.1-100%) were seroconverted, and 82.8% (24/29) had anti-HEV IgG levels higher than 1.0 WU/ml at one month after the final dose (median, 38 days, IQR: 31-44). CONCLUSIONS: This study suggests that Hecolin is safe and immunogenic in CHB patients with compensated liver cirrhosis, supporting its use in preventing HEV superinfection in this high-risk population.