A 60-year old woman was admitted for reintroduction of interferon/ribavirin combination therapy to prevent the recurrence of hepatitis C following living donor liver transplantation (LDLT). She had also undergone splenectomy during LDLT to avoid postoperative pancytopenia due to hypersplenism. However, a few days after reintroduction of the therapy, she developed severe diarrhea and fever that progressed to circulatory and respiratory shock. Blood culture was positive for Streptococcus pneumoniae, leading to a diagnosis of overwhelming postsplenectomy infection (OPSI). Although the patient developed multi-organ failure, she ultimately recovered after intensive care including mechanical ventilation and hemodialysis. Once OPSI is suspected, intensive care should be commenced immediately given the disease' s fulminant clinical course and high mortality. Postoperative prophylaxis with the pneumococcal vaccine needs to be tested in a multi-center study.