BACKGROUND: Acute pain episodes in children with sickle cell disease (SCD) represent a leading cause of readmissions. We examined prescription practices at the time of discharge in children with SCD presenting with acute pain to determine their impact on 30-day emergency department (ED) revisits and readmissions. METHODS: In this single-institution, 5-year retrospective study, we reviewed 290 encounters of patients with SCD aged 7-21 years hospitalized or discharged from the ED with acute pain. We reviewed demographic, treatment and discharge data, and 30-day returns, defined as ED revisits and readmissions within 30 days of discharge. Bivariate and multivariable analyses were performed to evaluate the association between discharge prescription practices and 30-day returns. RESULTS: Compared to hospitalizations, treat-and-release ED visits for acute pain were associated with a higher incidence of 30-day returns (OR = 2.7 [95% CI: 1.5-4.8], P < 0.01). We found no association between prescribed opioid frequency (scheduled vs. as-needed) and 30-day returns (OR = 1.12 [95% CI: 0.62-2.02], P = 0.70). By multivariable logistic regression, the prescription of nonsteroidal anti-inflammatory drugs (NSAIDs) only, without opioids, after treat-and-release ED visits was independently associated with a higher frequency of 30-day ED revisits (OR = 6.9 [95% CI: 1.3-37.3], P = 0.03) but not readmissions. CONCLUSION: Variability exists in opioid prescription practices after discharge in children with SCD and pain episodes. Prescription of NSAIDs only, without opioids, was an independent predictor of higher 30-day ED revisits. Formalized studies to better understand factors that influence returns, including outpatient opioid management, are warranted in this population.