Respiratory syncytial virus (RSV) causes seasonal epidemics of bronchiolitis among susceptible infants. Surfactant protein A (SP-A), a lung C-type lectin involved in innate host defense, opsonizes RSV and enhances phagocytosis. The candidate gene approach was used to investigate association of SP-A polymorphism with susceptibility to severe RSV infection. Genotype analysis was done for 86 infants with severe RSV infection and 95 matched control subjects. A significant difference in the frequency of SP-A2 was observed. The SP-A2 allele 1A(3) was overrepresented in RSV-infected infants, compared with control subjects (5% vs. 0.5%; P =.006), whereas allele 1A was underrepresented (1% vs. 6%; P =.011). The allele pool in which lysine was amino acid 223 was overrepresented in infants with severe RSV infection (28% vs. 18%; P =.023), whereas the allele pool in which proline was amino acid 99 was underrepresented (5% vs. 16%; P =.001). These results indicate that a genetic association exists between SP-A gene locus and severe RSV infection.