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Nirmatrelvir is an orally administered anti -SARS-CoV-2 drug used in combination with ritonavir, the drug-metabolizing cytochrome P450 (CYP) 3A inhibitor, to evade metabolism and extend bioavailability. Meanwhile, the immunosuppressant tacrolimus is a CYP3A4/5 substrate, and CYP3A inhibition results in drug-drug interactions. Herein, we report the case of a coronavirus disease 19 (COVID-19) patient in the maintenance phase post liver transplantation, receiving tacrolimus treatment, with a marked increase of blood tacrolimus levels after the initiation of concomitant nirmatrelvir/ritonavir treatment. A 61-year-old Japanese woman underwent a living donor liver transplant for Caroli disease 25 years ago and received tacrolimus 2 mg/day for immunosuppressive treatment. Three days before the observed high tacrolimus blood concentration, she presented to our emergency department with a fever and was diagnosed with COVID-19. She was prescribed an adjusted dose of nirmatrelvir/ritonavir (150 mg/100 mg, twice daily) for 5 days as a high-risk case with immunosuppressive treatment and reduced renal function (estimated glomerular filtration rate, eGFR: 46.6 mL/min/1.73 m2). At the return visit on day 1, blood tacrolimus level was >60 ng/mL on trough sampling, above the upper limit of measurement, with nausea and vomiting as side effects. Tacrolimus treatment was discontinued on the same day. Drug-drug interactions resulting from CYP3A inhibition by nirmatrelvir/ritonavir were deemed responsible for elevated blood tacrolimus levels. Therefore, in liver transplant recipients, tacrolimus dose reduction or discontinuation is required during COVID-19 treatment with nirmatrelvir/ritonavir. [ABSTRACT FROM AUTHOR]