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Background & Aims The global pandemic caused by the highly contagious SARS-CoV-2 virus led to the emergency approval of COVID-19 vaccines to reduce rising morbidity and mortality. However, limited research exists on evaluating the impact of these vaccines on immunocompromised individuals, such as recipients of living donor liver transplantation, highlighting the need for further studies to better understand their effectiveness in this specific population. Methods From June 2021, we followed up on the effectiveness of the vaccine for patients taking immunosuppressive drugs after living-donor liver transplantation (LDLT). A total of 105 immunocompromised individuals participated, of which 50 patients with hepatitis B were taking antiviral drugs. Patients were assessed to analyze how the combination of immunosuppressive and antiviral drugs affected the efficacy of the BNT162b2, mRNA-1273, and ChAdOx1 nCoV-19 COVID-19 vaccines. Results Before and after the vaccinations, patients were monitored to establish differences between immunosuppressed patients and those additionally taking antiviral drugs. In immunocompromised patients taking antiviral drugs for hepatitis B, we confirmed that the effect of the COVID-19 vaccine was reduced when compared to immunocompromised patients. Interestingly, 23 patients (11 without and 12 additionally with hepatitis B drug administration) encountered breakthrough infections, and although there was a minor discrepancy in vaccine efficacy among the patients taking antiviral drugs for hepatitis B, it did not reach statistical significance. Conclusions Additional COVID-19 vaccination is recommended for patients taking immunosuppressive drugs and hepatitis B antiviral drugs after LDLT.