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Asthma is associated with increases in sickle cell disease (SCD)-related morbidity and mortality. A thorough evaluation for asthma in children with SCD is important and may involve methacholine challenge (MCh). In this report, we present a 14-year-old male with SCD who was admitted for an acute painful episode following MCh. Pain events after MCh have not been previously reported in children with SCD. The risk-benefit ratio should be strongly considered prior to performance of MCh in this patient population, and all possible complications, including an acute painful episode, should be openly discussed with the parents and pediatric patient.