Post-transplant malignancy is the major cause of later death of recipients after liver transplantation. Tumor recurrence after liver transplantation for patients with hepatocellular carcinoma in the end stage of cirrhosis has been frequently encountered. However, de novo hepatocellular carcinoma originating from the liver allograft has only rarely been reported. Here we reported a case of de novo hepatocellular carcinoma developed 2 years after living donor liver transplantation for hepatitis B-related liver cirrhosis with viral YMDD mutation. To the best of our knowledge, this is the first report of de novo hepatocellular carcinoma in a liver graft with recurrent hepatitis B virus infection after liver transplantation for hepatitis B-related liver cirrhosis with YMDD mutation. Moreover, the de novo cancer first presented as a lung mass with minimal liver involvement and was obscured by a pulmonary fungal infection.