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Premature and other at-risk infants can experience cardiorespiratory problems when positioned in their car seats. The American Academy of Pediatrics recommends that all premature and at-risk infants undergo a period of observation in their car seat to monitor for apnea, bradycardia, and oxygen desaturation before hospital discharge. This Infant Car Seat Challenge (ICSC) is used to determine readiness for infant travel in a car seat. Infants failing the ICSC are discharged home in car beds and referred for a follow-up screen in the outpatient clinic.The purpose of this study was to identify predictors for infants failing the follow-up ICSC after hospital discharge.A retrospective, cross-sectional study design was used to examine charts of 436 infants referred from across New England, to Boston Children's Hospital's, Center for Healthy Infant Lung Development clinic between August 2008 and May 2015 for a follow-up ICSC.Infants who failed the follow-up ICSC had statistically significant lower weights (0.27 ± 0.14 kg, difference ± standard error, P = .03) and younger postmenstrual ages (0.9 ± 0.4 weeks, P = .03). History of a cardiac condition (odds ratio, 3.6; 95% confidence interval, 1.5-8.5; P = .005) and respiratory illness (odds ratio, 2.1; confidence interval, 1.1 to 4.2; P = .03) were significant predictors of ICSC failure.A follow-up ICSC is recommended for the safe transition of infants from a car bed to a car seat.Further research is needed to investigate the causes of ICSC failure among high-risk infant populations.