Francisella tularensis is an intracellular gram-negative bacterium and the etiological agent of pulmonary tularemia. Given the high degrees of infectivity in the host and of dissemination of bacteria following respiratory infection, immunization strategies that target mucosal surfaces are critical for the development of effective vaccines against this organism. In this study, we have characterized the efficacy of protective immunity against pneumonic tularemia following oral vaccination with F. tularensis LVS (live vaccine strain). Mice vaccinated orally with LVS displayed colocalization of LVS with intestinal M cells, with subsequent enhanced production of splenic antigen-specific gamma interferon and of systemic and mucosal antibodies, including immunoglobulin A (IgA). LVS-vaccinated BALB/c mice were highly protected against intranasal (i.n.) SCHU S4 challenge and exhibited significantly less bacterial replication in the lungs, liver, and spleen than mock-immunized animals. Depletion of CD4(+) T cells significantly abrogated the protective immunity, and mice deficient in B cells or IgA displayed partial protection against SCHU S4 challenge. These results suggest that oral vaccination with LVS induces protective immunity against i.n. challenge with F. tularensis SCHU S4 by a process mediated cooperatively by CD4(+) T cells and antibodies, including IgA.