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Objective: We evaluated the ability of intravenous (IV) acetaminophen to reduce the amount of opioid medication administered in pediatric patients with sickle cell disease (SCD) having vasoocclusive crisis (VOC) in an emergency department (ED) setting. Methods: This was a prospective, randomized, double‐blind placebo‐controlled trial at an academic urban pediatric ED. Participants included patients with SCD, aged 4 to 16 years, with VOC pain. All patients received a 0.1 mg/kg dose of IV morphine, 0.5 mg/kg ketorolac, or both. Patients were randomized to receive either 15 mg/kg IV acetaminophen or placebo. Patients were reassessed every 30 minutes to see whether additional opioid doses were indicated to a maximum of three doses. The total morphine given, pain scores, rates of admissions, 72‐hour return visits, and adverse events were assessed for each group. Results: Of 71 subjects randomized, 35 patients in the acetaminophen group and 36 patients in the control group were analyzed. Baseline characteristics and initial pain scores were similar in both groups. The mean total amount of morphine given was 8.6 mg (95% confidence interval [CI] = 6.5 to 10.8) in the acetaminophen group and 8.0 mg (95% CI = 5.9 to 10.2) in the placebo group. The mean total cumulative morphine dosing was 0.2 mg/kg (95% CI = 0.1 to 0.2 mg/kg) in the acetaminophen group and 0.2 mg/kg (95% CI = 0.1 to 0.2 mg/kg) in the control group. The mean pain score at time of disposition was 5.5 (95% CI = 4.3 to 6.6) in the acetaminophen group and 5.2 (95% CI = 4.2 to 6.3) in the placebo group. There were no clinical or statistically significant differences between the rates of admission, 72‐hour return visits, or adverse events. Conclusion: In this study, patients who received IV acetaminophen did not receive less morphine than patients in the placebo group. Disposition pain scores for the two groups were also equivalent. We conclude that IV acetaminophen, when used in addition to morphine for pediatric sickle cell VOC pain, does not provide an opioid‐sparing effect. Further searches for adjunctive nonaddictive pain medicines are indicated. [ABSTRACT FROM AUTHOR]