Extract: Transformation and increased mitotic activity in donor lymphocytes exposed to specific antigens is considered by many to be a manifestation of cell-mediated immunity. In attempts to understand the apparent “sensitization” of individuals to respiratory syncytial virus (RSV) as a result of receiving inactivated RSV vaccine, in vitro lymphocyte transformation studies were carried out on infants who had received inactivated RSV vaccine and on infants who had received a similarly prepared inactivated African green monkey kidney (AGMK) cell-grown parainfluenza type 1 virus vaccine or a trivalent parainfluenza vaccine prepared in hen's eggs. Each group included some infants who had, and others who had not, undergone natural RSV infection under our observation before the lymphocyte studies. Lymphocytes were studied from 21 infants and young children who had received the inactivated RSV vaccine, 14 who received a similarly prepared inactivated parainfluenza 1 vaccine, and 5 who received a trivalent parainfluenza vaccine. Twelve of the RSV vaccinees and 14 of the parainfluenza vaccinees had been naturally infected with RSV as indicated by virus recovery and/or antibody rise between the time of vaccination and the lymphocyte studies. In comparing the arithmetic mean for RSV-specific transformation and mitotic activity there was a significant difference between RSV vaccinees and parainfluenza vaccinees whether one compared those who had undergone natural RSV infection or those who had not undergone natural infection. The difference between RSV vaccinees who had not undergone natural RSV infection and RSV-infected parainfluenza vaccinees also was significant. There was a greater level of transformation and mitotic activity in those who had experienced natural infection than those who had not among both RSV vaccinees and parainfluenza vaccinees, but these differences were not significant statistically. Speculation: We take these findings to mean that natural RSV infection probably stimulates a systemic cell-mediated immunity response and that such a response is definitely induced after administration of killed RSV antigen. These findings are consistent with the hypothesis that cell-mediated sensitization may in some way contribute to the altered response to natural infection which occurred after use of inactivated RSV vaccine. Our findings do not support the hypothesis that systemic cell-mediated immunity per se is important in protecting against RSV infection. The findings also suggest the possibility that transplacentally conferred RSV lymphocyte sensitization might play a part in the pathogenesis of nonvaccine related RSV bronchiolitis which characteristically occurs during early infancy, frequently in the presence of measurable serum antibody.