Background. This work compared the efficacy and safety of oral versus intravenous morphine in children with sickle cell pain.Methods. 56 children received intravenous morphine LD≤50.15 mg/kg, followed by either oral morphine 1.9 mg/kg q12h plus intravenous placebo, or intravenous morphine 0.04 mg/kg/h, plus placebo tablet. Pain was assessed using 4 pain scales. Post-hoc analysis assessed exposure to morphine as an etiological factor for acute chest syndrome (ACS).Results. 50 children completed. Baseline demographic/physiologic characteristics were similar between groups. Mean oral morphine dose was 2.99 mg/kg/d[0.75]; mean intravenous morphine dose was 0.81 mg/kg/d[0·30]). Mean pain scores were similar for both treatment groups. With oral morphine, there was a 2-fold higher morphine AUCSS and a 3-fold higher M6G AUCSS than with CIV morphine. New onset of ACS was 3-fold more prevalent in the oral versus CIV group.Conclusions. Oral morphine provided effective analgesia. In a small subset, the risk of ACS was associated with high systemic exposure to oral morphine.