Hemolytic anemia occurs in only 1% to 3% of hospitalized patients with infectious mononucleosis. The authors describe an 8-year-old girl without cervical lymphadenopathy or splenomegaly, who presented with conjugated hyperbilirubinemia and was diagnosed with cold agglutinin disease caused by an immunoglobulin M autoantibody with anti-i specificity. Acute Epstein-Barr virus infection was confirmed by serologic and molecular methods. She recovered uneventfully after a 3-week course of methylprednisolone. Epstein-Barr virus infection should be considered in any case of hemolytic anemia associated with hepatic dysfunction, especially when direct antiglobulin test is positive for C3d. In these cases, a course of corticosteroids seems safe and may be beneficial.