Lymphotoxin-α−/−(LTα−/−) mice are thought to be unable to generate effective T and B cell responses. This is attributed to the lack of lymph nodes and the disrupted splenic architecture of these mice. However, despite these defects we found that LTα−/− mice could survive infection with a virulent influenza A virus. LTα−/− mice and normal wild-type mice infected with influenza A generated similar numbers of influenza-specific CD8 T cells that were able to produce IFN-γ and kill target cells presenting influenza peptides. Furthermore influenza-infected LTα−/− mice produced high titers of influenza-specific IgM, IgG, and IgA. However, both CD8 and B cell immune responses were delayed in LTα−/− mice by 2–3 days. The delayed cellular and humoral immune response was sufficient to mediate viral clearance in LTα−/− mice that were infected with relatively low doses of influenza virus. However, when LTα−/− mice were infected with larger doses of influenza, they succumbed to infection before the immune response was initiated. These results demonstrate that neither LTα nor constitutively organized lymphoid tissues, such as lymph nodes and spleen, are absolutely required for the generation of effective immunity against the respiratory virus influenza A. However, the presence of LTα and/or lymph nodes does accelerate the initiation of immune responses, which leads to protection from larger doses of virus.