In response to three injections of alum precipitated, 100X concentrated, formalin inactivated RS vaccine (lot 100), 43% of infant vaccinees displayed a 4-fold or greater rise in serum neutralizing antibody and 91% displayed a 4-fold or greater rise in serum CF antibody. When RS virus became prevalent in the community, the rate of RS virus infection in infants who received this vaccine was not remarkably different from that in control infants who received parainfluenza vaccines. However, 80% of RS vaccinees required hospitalization at the time of RS infection whereas only 5% of such infections among parainfluenza vaccinees resulted in admission to the hospital. Illnesses among the RS vaccinees who underwent natural infection included pneumonia, bronchiolitis, and bronchiolitis with pneumonia in a majority and rhinitis, pharyngitis and bronchitis in a few. It seems clear that infants who received this vaccine were not protected against natural infection and also, when they became naturally infected their illness was more severe than that seen in cohorts who received a similar parainfluenza type 1 vaccine. These findings indicate that vaccine-induced RS virus serum antibody alone does not protect against illness and suggest that serum antibody without local respiratory antibody may play a part in the production of disease. We have also observed that the highest incidence of serious RS virus illness occurring naturally is under six months of age when maternally derived serum antibody is present. These findings together suggest that RS virus illness in infants is an immunologic phenomenon wherein the virus and serum antibody interact to produce severe illness.