OBJECTIVE: To determine whether the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene is associated with lung injury in children with community-acquired pneumonia. DESIGN: A prospective cohort of children diagnosed with community-acquired pneumonia. SETTING: Two pediatric hospitals. PATIENTS: Eight hundred fifty pediatric patients with community-acquired pneumonia were enrolled. INTERVENTIONS: Genotyping of the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene was performed on DNA isolated from whole blood. MEASUREMENTS AND MAIN RESULTS: The requirement for positive pressure ventilation or the diagnosis of acute lung injury or acute respiratory distress syndrome were the main outcomes of the study. Children (14 days-19 yrs) with community-acquired pneumonia (850) were enrolled; analysis was limited to African American (515) and Caucasian (232) patients. Of the 82 patients requiring positive pressure ventilation, 44 were diagnosed with acute lung injury or acute respiratory distress syndrome. Multivariate logistic regression analyses indicated that children without a copy of the A1 allele of the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene were more likely to need positive pressure ventilation compared to those with one or two copies of this allele (odds ratio = 2.65, confidence interval, 1.02-6.90). In addition, the absence of the A1 allele also appeared to be associated with the development of community-acquired pneumonia-induced acute lung injury/acute respiratory distress syndrome (odds ratio = 3.1, confidence interval, 0.99-9.67). CONCLUSIONS: In children with community-acquired pneumonia, absence of the A1 allele at the interleukin-1 receptor antagonist intron 2 polymorphic site is associated with increased risk for more severe lung injury, as measured by the need for positive pressure ventilation or the development of acute lung injury or acute respiratory distress syndrome. Conversely, presence of the A1 allele is associated with decreased risk for more severe lung injury in this patient population.