CD1d-deficient mice have normal numbers of T lymphocytes and natural killer cells but lack Vα14⁺ natural killer T cells. Respiratory syncytial virus (RSV) immunopathogenesis was evaluated in 129×C57BL/6, C57BL/6, and BALB/c CD1d^−/− mice. CD8⁺ T lymphocytes were reduced in CD1d^−/− mice of all strains, as shown by cell surface staining and major histocompatibility complex class I tetramer analysis, and resulted in strain-specific alterations in illness, viral clearance, and gamma interferon (IFN-γ) production. Transient activation of NK T cells in CD1d^+/+ mice by α-GalCer resulted in reduced illness and delayed viral clearance. These data suggest that early IFN-γ production and efficient induction of CD8⁺-T-cell responses during primary RSV infection require CD1d-dependent events. We also tested the ability of α-GalCer as an adjuvant to modulate the type 2 immune responses induced by RSV glycoprotein G or formalin-inactivated RSV immunization. However, immunized CD1-deficient or α-GalCer-treated wild-type mice did not exhibit diminished disease following RSV challenge. Rather, some disease parameters, including cytokine production, eosinophilia, and viral clearance, were increased. These findings indicate that CD1d-dependent NK T cells play a role in expansion of CD8⁺ T cells and amplification of antiviral responses to RSV.