Nirmatrelvir/ritonavir, a newly authorized drug for the treatment of COVID-19, is a strong CYP3A4 inhibitor, which can interact with a large number of drugs, such as tacrolimus, reducing its metabolism. The reported case is a renal transplant patient who experienced a strong increase in tacrolimus blood concentration (up to 112ng/ml, more than ten times the reference range) when treated with both drugs at the same time, which caused a neurological condition that required hospital admission its control and treatment. The resolution of the symptoms was rapid, but the elevation of tacrolimus concentration remained for several days, even after discontinuation of both drugs. This study shows the importance of developing a protocol for the management of this interaction to guarantee the efficacy and safety of treatment with nirmatrelvir/ritonavir in transplant patients.