Previous reports have suggested that peroral delivery of antigens chemically coupled to non-toxic recombinant enterotoxin B subunits, such as the cholera toxin B subunit (CTB), induces tolerance to the antigen that may be abrogated by the toxic enzyme activity of intact enterotoxins, such as cholera toxin (CT). The aim of this study was to examine the immunogenicity of a genetically coupled protein composed of the saliva-binding region (SBR) of the Streptococcus mutans surface antigen AgI/II and the non-toxic A2 and B subunits of CT (SBR-CTA2/B) compared with that of recombinant SBR admixed with CT (SBR + CT) and SBR chemically coupled to recombinant CTB (SBR-CTB) following peroral delivery by intragastric (i.g.) immunization. The results showed that i.g. immunization with SBR-CTA2/B, like SBR + CT, induced antigen-specific serum immunoglobulin G (IgG) and salivary IgA antibodies, and sensitized splenic T cells. Comparison studies with SBR-CTB produced serum IgG but not salivary IgA titres and failed to sensitize splenic cells. Immunization with SBR-CTA2/B via the intranasal route also primed for the recall of antigen-specific memory antibody responses 6 months later. These findings show that SBR-CTA2/B is an immunogenic, not tolerogenic, chimeric protein that can induce and recall antigen-specific memory responses upon mucosal immunization.