We report a case of blood exchange transfusion to treat acute liver failure following hepatitis B infection at the Infectious Disease Department of Children's Hospital No.2 in Ho Chi Minh City, Vietnam. A 3.5-month old baby boy was admitted to the hospital with a presentation of progressively worsening jaundice for the past one month. The patient was diagnosed with hepatitis B infection with a positive HBV DNA quantitative assay. Plasma exchange was indicated in view of progressive liver failure and gradually increasing hepatic coma. However, it was impossible to perform plasmapheresis in this case because the patient was small (in terms of age and weight) and there was no suitable plasma exchange filter. Accordingly, the patient was treated with 3 times of blood exchange transfusion in combination with an antiviral drug, lamivudine. After each blood exchange transfusion, the biochemical values (bilirubin, liver enzymes, and coagulation profile) gradually improved and he was discharged after 1 month of treatment. Blood exchange transfusion is an effective procedure for managing acute liver failure, where plasma exchange is not possible while waiting for the recovery of liver functions or liver transplantation.