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Context: Down syndrome (DS) is the most common chromosomal condition in live-born infants worldwide, and lower respiratory infection caused by respiratory syncytial virus (RSV) is a leading cause of hospital admissions., Objective: To evaluate RSV-associated morbidity among children with DS compared with a population without DS., Data Sources: Four electronic databases were searched., Study Selection: All cohorts or case-control studies of DS with an assessment of RSV infection and the associated morbidity or mortality were included without language restriction., Data Extraction: Two reviewers independently reviewed all studies. The primary outcomes were hospital admission and mortality. Secondary outcomes included length of hospital stay, oxygen requirement, ICU admission, need for respiratory support, and additional medication use., Results: Twelve studies ( n = 1 149 171) from 10 different countries met the inclusion criteria; 10 studies were cohort studies, 1 study was retrospective, and 1 study had both designs. DS was associated with a higher risk of hospitalization (odds ratio [OR]: 8.69; 95% confidence interval [CI]: 7.33-10.30; I 2 = 11%) and mortality (OR: 9.4; 95% CI: 2.26-39.15; I 2 = 38%) compared with what was seen in controls. Children with DS had an increased length of hospital stay (mean difference: 4.73 days; 95% CI: 2.12-7.33; I 2 = 0%), oxygen requirement (OR: 6.53; 95% CI: 2.22-19.19; I 2 = 0%), ICU admission (OR: 2.56; 95% CI: 1.17-5.59; I 2 = 0%), need for mechanical ventilation (OR: 2.56; 95% CI: 1.17-5.59; I 2 = 0%), and additional medication use (OR: 2.65 [95% CI: 1.38-5.08; I 2 = 0%] for systemic corticosteroids and OR: 5.82 [95% CI: 2.66-12.69; I 2 = 0%] for antibiotics) than controls., Limitations: DS subgroups with and without other additional risk factors were not reported in all of the included studies., Conclusions: Children with DS had a significantly higher risk of severe RSV infection than children without DS., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)