Antigenic differences between the two major groups of respiratory syncytial (RS) virus may contribute to reinfections with these viruses. Additional variability occurs within the two major groups; the importance of intra-group variability in reinfections with RS virus has not been defined. Two pairs of group A viruses that had caused sequential infections in children showed G protein amino acid differences of up to 15%. Vaccinia viruses were constructed that expressed the G proteins from 2 of the paired group A isolates. Immunization of cotton rats with the recombinant vaccinia viruses provided equal protection against intranasal challenge by either of the RS viruses. Despite the amino acid differences between the two group A RS virus G proteins, these animal studies did not reveal differences in protection after immunization with the two G proteins. Precise definition of the role of RS virus antigenic variability in the establishment of reinfections in humans will require further investigations in humans.