We sought to characterize the human respiratory syncytial virus (RSV) subgroup-specific antibody response to primary infection with RSV. RSV isolates from 43 infants and young children were typed as either subgroup A (Long strain-like) or B (18537 strain-like) based on reactivity with monoclonal antibodies. Acute-phase or preinfection and convalescent-phase sera were collected from the 43 subjects and tested in an enzyme-linked immunosorbent assay using purified F and G glycoproteins from RSV subgroups A and B and by neutralization assay against both subgroups of RSV. Twenty-six individuals had rises in titer of antibody to F glycoprotein, 27 to G glycoprotein, and 28 had rises in titer of neutralizing antibody. The antibody responses to homologous and heterologous F glycoproteins were not significantly different. In contrast, homologous vs. heterologous antibody responses to G glycoprotein were significantly different, with 7.3% relatedness between the G glycoproteins of subgroups A and B. Analysis of neutralizing antibody responses revealed 31% relatedness.