Akinetic mutism is an uncommon clinical syndrome characterized by the inability to produce voluntary movements or speech without loss of awareness. Cerebrovascular diseases are the most frequent etiology. It has been reported in cyclosporine-related neurotoxicity, but it is exceptional as the presenting form of tacrolimus intoxication. We report the case of a 66-year-old man who underwent an orthotopic liver transplantation and was treated with intravenous methylprednisolone and tacrolimus. He had an uneventful postoperative course until the third day after surgery, when he developed acute onset mutism, akinesia, and waxy rigidity of passive limb movements. His arterial blood pressure and temperature were normal. Blood analysis and a magnetic resonance image of the brain showed no acute abnormalities. Serum levels of tacrolimus were 20.8 ng/mL, so it was substituted by cyclosporine and mycophenolate mofetil with progressive and complete recovery of akinetic mutism during the following days. Akinetic mutism is an exceptional manifestation of tacrolimus neurotoxicity, but early recognition of the syndrome and withdrawal of the drug are important to avoid persistent cerebral lesions.