Evaluation of a patient prompted the systematic review of causes of abrupt onset anemia in children and the development of a protocol for the immunohematologic workup of such cases. The patient, a 3-year-old boy, presented to our institution two weeks following a viral illness with gross hematuria, jaundice, and severe anemia (hematocrit 14.5%). He was found to have a positive direct antiglobulin test (DAT) due to primarily complement sensitization (2+) with smaller amounts of IgG (weak). A nonspecific cold agglutinin, anti-P1, and a hemolytic biphasic Donath-Landsteiner antibody were demonstrated in his serum, and he was diagnosed with paroxysmal cold hemoglobinuria (PCH). The hemolytic anemia resolved with packed red cell transfusions, intravenous immune globulin, and steroid treatment. It was concluded that a complete immunohematologic evaluation, including a DAT, cold agglutinin, and Donath-Landsteiner antibody tests, is pivotal to prompt and accurate assessment of the cause of an abrupt onset of severe anemia in children.