The experiments described establish that CD4+ T-cell-dependent effector mechanisms can eliminate an H3N2 influenza A virus from lung cells that are unable to express class II major histocompatibility complex (MHC) glycoproteins. Radiation chimeras were made by using CD4+ T cells and bone marrow from CD8-depleted, MHC class II +/+ mice and irradiated (950 rads) MHC class II -/- recipients. The influenza virus-specific CD4+ T-cell responses in these +/+-->-/- mice were not obviously different from those in the +/+-->+/+ controls: the cytokine profiles, the spectra of plasma cells producing the various immunoglobulin isotypes, and the frequencies of virus-specific CD4+ T cells were similar for the two groups. Expression of class II MHC glycoproteins on stimulator cells, B lymphocytes, and monocytes/macrophages is apparently sufficient for CD4+ T cells to terminate influenza virus infection of MHC class II -/- respiratory epithelium. A possible explanation is that the local spread of this lytic virus in the lung is limited by cytokines and/or antibody.