Prostaglandin I 2 (PGI 2 ) protects against RSVinduced illness in mice. A variable-number tandem repeat (VNTR) polymorphism has been detected in the promoter region of the PGI 2 synthase (PGIS) gene. We sought to determine if PGI 2 concentrations or polymorphisms of the PGIS gene correlate with severity of RSV lower respiratory tract infections (LRTI) in human infants. VNTR polymorphisms were studied in 81 previously healthy children between birth and 12 months of age who were hospitalized for LRTI due to RSV and 98 healthy adult control subjects. The severity of RSV infection was quantified using a clinical scoring system, and infant urine samples were collected during the acute illness for measurement of the urinary metabolite of PGI 2 . There were no significant differences in the overall distribution of alleles and genotypes between infants with RSV LRTI and the control subjects. The severity of RSV infection significantly inversely correlated with urinary PGI 2 metabolite concentrations. The urinary PGI 2 metabolite concentration correlated with the number of VNTR. The presence of a genotype with a low number VNTR repeats significantly correlated with the most severe RSV LRTI, and genotypes with the highest number of VNTR correlated with the least severe RSV LRTI. A functional polymorphism in the promoter region of the PGIS gene is associated with both significant differences in urinary PGI 2 concentrations during RSV LRTI, and severity of RSV infection in previously healthy infants.