OBJECTIVE: To determine whether genetic variations in the gene coding for surfactant protein B are associated with lung injury in African American children with community-acquired pneumonia. DESIGN: A prospective cohort genetic association study of lung injury in children with community-acquired pneumonia. SETTING: Two major tertiary care children's hospitals. SUBJECTS: African American children with community-acquired pneumonia (n = 395) either evaluated in the emergency department or admitted to the hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred ninety-five African American children (14 days to 18 yrs of age) with community-acquired pneumonia were enrolled. Thirty-seven patients required mechanical ventilation and 26 of these were diagnosed with acute lung injury or acute respiratory distress syndrome. Genotyping was performed on seven linkage disequilibrium-tag single nucleotide polymorphisms in the surfactant protein B gene. Univariate analysis demonstrated two linkage disequilibrium-tag single nucleotide polymorphisms, rs1130866 (also known as SP-B + 1580 C/T) and rs3024793, were associated with the need for mechanical ventilation in African American children (p = .016 and p = .030, respectively). Multivariable analysis indicated that both of these single nucleotide polymorphisms are independently associated with need for mechanical ventilation (p = .040 and p = .012, respectively) as was rs7316 when its interaction with age was considered (p = .015). Multivariable analysis examining acute lung injury demonstrated a significant association of rs7316 with acute lung injury (p = .031). Haplotype analysis was also performed. Two haplotypes, GTGCGCG and ATATAAG, were associated with need for mechanical ventilation using either univariate (p = .041 and p = .043, respectively) or multivariable analysis (odds ratios of 2.62, p = .048, and 3.12, p = .033, respectively). CONCLUSIONS: Genetic variations in the gene coding for surfactant protein B are associated with more severe lung injury as indicated by the association of specific single nucleotide polymorphism genotypes and haplotypes with the need for mechanical ventilation in African American children with community-acquired pneumonia.