Despite azvudine being prioritized for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, its effectiveness and safety remain inadequately substantiated in hospitalized SARS-CoV-2 infected patients with liver diseases. A retrospective nine-center cohort study along with an independent validation cohort is conducted to examine the efficacy of azvudine (Clinical Trial Registration Number: NCT06349655). The primary outcome is all-cause mortality and the secondary outcome is composite disease progression. Efficacy is assessed via Kaplan-Meier analysis and Cox regression, with subgroup and sensitivity analyses for further validation. Among 32 864 hospitalized SARS-CoV-2 infected patients, 1022 eligible azvudine recipients, and 1022 controls are included through propensity score match. Kaplan-Meier analysis reveals that azvudine treatment is associated with a lower risk of all-cause mortality and composite disease progression (both p<
0.0001). Cox regression analysis suggests azvudine recipients could have a 39% lower risk of all-cause mortality than controls (95% confidence interval [CI]: 0.468-0.795, p<
0.001), but with no notable significance in composite disease progression (hazard ratio: 0.85, 95% CI: 0.686-1.061, p = 0.154). Subgroup analysis suggests that azvudine has a greater benefit for both all-cause mortality and composite disease progression in patients with kidney diseases or without autoimmune diseases. Three sensitivity analyses and validation cohorts confirm the robustness of the findings. Safety analysis observes few adverse events in azvudine recipients. Within 15 days after azvudine administration, no significant difference in liver function indexes and kidney function indexes is observed between the two groups except for a few time points. These findings demonstrate that azvudine shows potential clinical efficacy in improving all-cause mortality in hospitalized SARS-CoV-2 infected patients with liver diseases, with acceptable adverse effects.