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Pediatric perioperative cardiac arrest (CA) is a rare but catastrophic event. This case–control study aims to analyze the causes, incidence, and outcomes of all pediatric CA reported to Wake Up Safe. Factors associated with CA and mortality after arrest are examined and possible strategies for improving outcomes are considered.CA in children was identified from the Wake Up Safe Pediatric Anesthesia Quality Improvement Initiative, a multicenter registry of adverse events in pediatric anesthesia. Incidence, demographics, underlying conditions, causes of CA, and outcomes were extracted. Descriptive statistics and logistic regression were used to study the above factors associated with CA and mortality after CA.A total of 531 cases of CA occurred during 1,006,685 anesthetics. CA was associated with age (odds ratio [95% confidence interval] comparing ≥6 vs <6 months of 0.26 [0.22–0.32]; P = .014), American Society of Anesthesiologists physical status (ASA PS III–V versus I–II, 9.24, 7.23–11.8; P < .001), and emergency status (3.55, 2.88–4.37; P < .001). Higher ASA PS was associated with increased mortality (ASA PS III–V versus I–II, 3.25, 1.20–8.81; P = .02) but anesthesia-related arrests were correlated with lower mortality (0.44, 0.26–0.74; P = .002). ASA emergency status (1.83, 1.05–3.19; P = .03) and off hours (night and weekend versus weekday, 2.17, 1.22–3.86; P = .008) were other factors associated with mortality after CA.The Wake Up Safe data validate single-institution studies’ findings regarding incidence, factors associated with arrest, and outcomes of pediatric perioperative CA. However, CA occurring during the off hours had significantly worse outcomes, independent of patient physical status or emergency surgery. This suggests an opportunity for improved outcomes.