Introduction: Hyperhemolytic crisis is a rare and dangerous complication of sickle cell disease where the hemoglobin level drops rapidly. This can quickly lead to organ failure and death. In the literature, most cases of hyperhemolysis in sickle cell patients followed a red cell transfusion. Case Summary : In this article, we report a case of a 6-year-old African American boy with sickle cell disease who presented with fever, increased work of breathing, and consolidation in the left lower lobe of the lung on chest X-ray. He initially improved with oxygen, fluids, and antibiotics but his hemoglobin acutely dropped from 7.6 to 6 g/dL the next day of admission. He was not previously transfused, and his reticulocyte count remained high. Subsequent transfusion recovered his hemoglobin. Conclusion : This case demonstrates that in the background of the chronic hemolysis of sickle cell disease, an acute anemia should warrant exploration of aplastic crisis (parvovirus infection), immune hemolytic anemia, hepatic sequestration crisis, splenic sequestration crisis, and hyperhemolytic crisis as possible etiologies. Ongoing reticulocytosis and a source of infection may direct suspicion especially toward hyperhemolytic crisis even without preceding red cell transfusion. We propose that the optimum management should include full supportive care (including transfusions if necessary) and treatment of the underlying cause of hemolysis (such as infections or drug exposure).