Pneumonia induced in cotton rats (Sigmodon hispidus) after inoculation of respiratory syncytial virus (RSV) was accompanied by the appearance of leukocytes in infected lungs. The number of these leukocytes increased until Day 5 after inoculation when sixfold more leukocytes were recovered from infected lungs using transpleural lavage than were recovered from lungs of uninfected control animals. Although macrophages and lymphocytes constituted approximately 65 and 25%, respectively, of the cells observed in lavage suspensions from both infected and uninfected lungs, only leukocytes in suspensions from infected animals appeared to be activated, as judged by cellular morphologic examination, cytochemical staining, and bactericidal activity. Leukocytes from lungs and adjacent lymph nodes of infected cotton rats, but not similar cells from uninfected animals, caused significant chromium release when they were added to primary cotton rat embryo and Hep-2 tissue culture cells infected with RSV in cytotoxicity assays. Cytotoxic activity peaked 5 days after inoculation, was neither virus-specific nor H-2 restricted, and was associated with both adherent and nonadherent fractions of lung cells. There was a close temporal relationship between the appearance of cytotoxic activity in the lung and termination of virus replication in this organ, suggesting a role for cytotoxic effector cells in recovery from respiratory syncytial virus infection of cotton rats.