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Severe pertussis complicated by refractory hyperleukocytosis poses a critical therapeutic challenge in young infants, particularly when initial exchange transfusion fails to mitigate escalating leukocytosis. We report a 1.5-month-old, 4.3-kg infant with severe pertussis and marked hyperleukocytosis (white blood cell [WBC] count 57.52 × 10⁹/L) unresponsive to conventional exchange transfusion. Paradoxically, WBC count increased to 48.07 × 10⁹/L with lymphocyte count rising to 12.69 × 10⁹/L post-exchange transfusion, necessitating emergency leukapheresis. After leukapheresis, the WBC count decreased to 25.87 × 10⁹/L and lymphocyte count to 4.71 × 10⁹/L; concurrently, peak flow velocity across the pulmonary valve declined from 2.09 to 0.90 m/s, reflecting hemodynamic improvement. With continued supportive care, the infant's WBC count gradually normalized and clinical recovery. This case illustrates that leukapheresis is a viable and effective therapeutic option for infants with severe pertussis complicated by refractory hyperleukocytosis when initial exchange transfusion is ineffective, providing clinical evidence for its use in neonates following unsuccessful exchange transfusion.