Immunization of mice with an attenuated Salmonella typhimurium strain (Phopc) carrying a plasmid encoding a hybrid form of the hepatitis B virus core antigen (HBc) induced specific antibody responses against the bacterial lipopolysaccharide (LPS) and HBc. Different mucosal routes of immunization, i.e., oral, nasal, rectal, and vaginal, were compared for their ability to induce a systemic as well as a mucosal response at sites proximal or distant to the site of immunization. Anti-LPS and anti-HBc immunoglobulin A (IgA) antibodies were measured in saliva, in feces, and in genital, bronchial, and intestinal secretions. Specific antibodies in serum and secretions were observed after immunization via all routes; however, the response to LPS was independent of that against HBc. In serum, saliva, and genital and bronchial secretions, high amounts of anti-HBc IgA were obtained by the nasal route of immunization. Vaginal immunization resulted in two different responses in mice: high and low. We observed a correlation between the level of specific immune response and the estrous status of these mice at the time of immunization. Rectal immunization induced high amounts of IgA against HBc and LPS in colonorectal secretions and feces but not at distant sites. These data suggest that S. typhimurium is able to invade different mucosal tissues and induce long-lasting local IgA responses against itself and a carried antigen after a single immunization.