Respiratory syncytial virus (RSV) causes seasonal outbreaks of respiratory tract infections, but the viral factors associated with virulence remain unknown. To determine whether RSV genotype correlated with severity of illness, isolates were characterized by phylogenetic analysis of the RSV G gene, and a composite score was used to quantify severity of illness. During the 1998-1999 and 1999-2000 winter seasons, 137 subgroup A and 84 subgroup B isolates were identified. The severity of illness caused by subgroup A isolates did not differ from that caused by subgroup B isolates (P=.086). However, the GA3 clade was associated with significantly greater severity of illness, compared with clades GA2 (P=.004) and GA4 (P=.016). In a subpopulation of patients < or =24 months old who had no known risk factors for severe RSV disease, clade GA3 was again associated with greater severity of illness, compared with clade GA2 (P=.018). Severity of RSV infection is associated with RSV genotype.