Antigenic group-specific serum antibody responses to first and second respiratory syncytial virus (RSV) infections were studied in children who had been followed longitudinally from early infancy in a research day-care center. Plaque-reduction neutralizing (PRN) antibody assays and ELISAs for the fusion (F) and attachment (G) glycoproteins were done using antigens of prototype RSV strains from groups A and B. Responses to antigens of viruses homologous and heterologous to the antigenic group of the infecting viral strain were compared. Primary group A infection elicited antibodies cross-reactive with group B virus in the PRNB and the ELISAS for GB and FB. In contrast, primary group B infection induced significant increases in mean concentrations of antibody cross-reactive with group A virus only in the FA ELISA. Second RSV infections caused by group B viruses in children with histories of primary group A infection induced heterologous rises in the PRNA and GA assays, suggesting that prior group A infection had primed for a more extensive cross-reacting antibody response at the time of second RSV infections with group B viruses.