Little information is available about the risk factors and means to improve the survival rate of acute leukemia in a rare but often fatal complication after liver transplantation (LT). We report the development of AML-M2 in one of the 764 patients who underwent liver transplantation at our center, and review the literature on similar cases. The patient, a 42-year-old man who developed acute leukemia 38 months after liver transplantation, was successfully treated with chemotherapy and has subsequently been in remission. With appropriate adjustment of immunosuppressive agents, he was able to safely benefit from chemotherapy. Only 16 patients with acute leukemia after liver transplantation have been reported, and the mortality rate is extraordinarily high (52.94%, 9/17). More cases of acute leukemia will emerge as the rate of survival after liver transplantation increases. The patient's chromosomal mutation profile, the choice of immunosuppressive agent, and infection by hepatitis virus may be the risk factors for the development of acute leukemia after LT. Our experience suggests that clinicians should adjust the immunosuppressive agents according to the immunosuppressive state of the patient and explore the option of reducing or stopping the medication as long as liver function remains stable. These measures could help reduce the high mortality rate among these patients.