Immunosuppressed recipients of liver transplantation (LT) are more likely to develop coronavirus disease 2019 (COVID-19) and may have an increased risk of developing worse outcomes.

To assess the effect of ursodeoxycholic acid (UDCA) on preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LT recipients.

Adult patients (aged ≥ 18 years) who underwent LT between 1 January 2015 and 31 December 2022 were included and categorized into two groups according to their use of UDCA.

The prevalence and severity of COVID-19 among transplantation patients between the UDCA and non-UDCA groups were estimated and compared.

Among the 897 LT patients who met the inclusion criteria, infection rate of SARS-CoV-2 was 78.4%, and the rate of severe illness was 5.1% from January 2022 to January 2023 in China. In the multivariate analysis, only UDCA treatment (P = 0.006) was found to be a protective factor against SARS-CoV-2 infection. After propensity score matching, the SARS-CoV-2 infection rate in the UDCA group was lower than that in the non-UDCA group (74.1% vs. 84.6%, P = 0.002). This rate was further reduced to 62.1% (P = 0.002) when the oral administration dose was >15 mg/kg/day. There was no difference in the rates of severe COVID-19 illness, ICU admission, or ventilation rate or length of hospital stay with or without UDCA treatment (all P > 0.05).

The use of UDCA in LT patients significantly reduced the SARS-CoV-2 infection rate and showed a dose-dependent protective effect.