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To determine the cumulative opioid doses administered to patients with Down syndrome after cardiac surgery and compare them with patients without Down syndrome.Retrospective observational comparative study.PICU in a university-affiliated freestanding pediatric teaching hospital.Infants and children who presented to our institution for heart surgery after July 1, 2008, and met the following criteria: 1) no opioid medications for 48 hours prior to surgery, 2) sternotomy approach with primary closure, and 3) no additional operative procedures in the 5 days after surgery. All patients with Down syndrome were included, and patients without Down syndrome with similar age, type of cardiac lesion, and length of surgical procedure were selected in a ~2:1 ratio, blinded to opioid exposure.None.Clinical and demographic data were extracted from electronic medical record data. Univariate analyses and multivariate linear regression modeling were performed to determine the influence of Down syndrome, patient characteristics, and clinical covariates on weight-adjusted opioid dose. The differences in median cumulative opioid doses between those with Down syndrome (n = 44) and those without Down syndrome (n = 77) were not significant in the first 24 hours (+0.39 mg/kg [95% CI, –0.45 to +1.39 mg/kg]) or 96 hours (+0.54 mg/kg [95% CI, –0.59 to +2.07 mg/kg]) after surgery. Age, cardiac bypass time, benzodiazepines, and neuromuscular blocking agents were significantly correlated with opioid dose, but Down syndrome, gender, pain score, creatinine, acetaminophen, nonsteroidal anti-inflammatory drugs, and steroid medications were not. Patients with Down syndrome had longer hospital stays; in multivariate analysis, higher opioid exposures in the first 96 hours after surgery and higher peak serum creatinine values correlated with longer hospitalization.This cohort did not provide evidence for opioid resistance in patients with Down syndrome. Younger age, longer cardiac bypass time, exposure to benzodiazepines, and neuromuscular blockade did correlate with increased opioid doses after cardiac surgery.