Aim: Pegylated-interferon/ribavirin/simeprevir (PEG-IFN/RBV/SMV) combination therapy is widely used for hepatitis C virus (HCV) treatment after liver transplantation (LT). Here, we observed two cases of extended severe anemia during PEG-IFN/RBV/SMV therapy for HCV serological type 1 re-infected after LT. Immunosuppressants consisted of tacrolimus and mycophenolate mofetil (MMF). Case 1 was a 65-year-old-woman treated with PEG-IFN/RBV/SMV therapy and 500 mg MMF/day 9 months after LT. Her serum hemoglobin (Hb) level decreased from 10 to 8.4 mg/dL on day 25. Despite discontinuing the PEG-IFN/RBV/SMV treatment on day 32, her Hb level decreased to 5.1 mg/dL on day 40. Case 2 was a 61-year-old-woman started on PEG-IFN/RBV/SMV therapy 20 months after LT. Her serum Hb level decreased from 12.2 to 7.1 mg/dL on day 39. The MMF dose was reduced from 1,500 to 1,000 mg/day, and her Hb level was maintained. Red blood cell transfusions were required in both cases, and anemia persisted for 2 months. These patients had the C/C major type inosine triphosphatase (ITPA) polymorphism. In conclusion, MMF induced severe persistent anemia by co-treatment with IFN/RBV in patients who underwent LT. Thus, the immunosuppressant dose should be chosen carefully for patients with the high-risk ITPA allele.