CD8⁺ cytotoxic T lymphocyte (CTL) activity, interferon (IFN)–γ, and interleukin (IL)–4 production were evaluated in a blinded manner among respiratory syncytial virus (RSV)–infected newborns and their mothers for 3 epidemic seasons. Most mothers (80%) exhibited RSV-specific CD8⁺ CTL activity. Twenty (80%) of the 26 infants exhibited significant RSV-specific CTL activity during or after their first RSV season. CTL frequency increased with RSV infection rate, reaching 75% by the end of the third season. Most infants who shed virus (75%) had a medically attended lower respiratory tract disease (LRD). In the first year, RSV-infected infants (virus culture and antibody increase) were more likely to develop CTL activity (10 of 13) than were uninfected infants (1 of 5; P=.02). Infants with CTL activity in the first year were less likely to have an LRD in the second year. CD8⁺ CTL levels correlated positively with IFN-γ (P<.001) and inversely with IL-4 (P=.03). Contribution of CD8⁺ CTL and IFN-γ in the control of RSV disease in infants and children is implicated