Although CD4⁺ T cells have been shown to mediate protective cellular immunity against respiratory virus infections, the underlying mechanisms are poorly understood. For example, although phenotypically distinct populations of memory CD4⁺ T cells have been identified in different secondary lymphoid tissues, it is not known which subpopulations mediate protective cellular immunity. In this report, we demonstrate that virus-specific CD4⁺ T cells persist in the lung tissues and airways for several months after Sendai virus infection of C57BL/6 mice. A large proportion of these cells possess a highly activated phenotype (CD44^hi, CD62L^lo, CD43^hi, and CD25^hi) and express immediate effector function as indicated by the production of interferon γ after a 5-h restimulation in vitro. Furthermore, intratracheal adoptive transfer of lung memory cells into β₂m-deficient mice demonstrated that lung-resident virus-specific CD4⁺ T cells mediated a substantial degree of protection against secondary virus infection. Taken together, these data demonstrate that activated memory CD4⁺ T cells persisting at mucosal sites play a critical role in mediating protective cellular immunity.