Streptococcus mutans is present in the saliva of most individuals and is modified by salivary components bound to the cells. These saliva-bound S. mutans are swallowed, exposed to high levels of acidity in the stomach, and presented to the common mucosal immune system. Much effort has been directed to identifying the specific S. mutans antigens that the mucosal immune responses are directed against. However, little is known about the host-altered antigenic determinants that the mucosal immune system recognizes. The immunogenicity of gastrically intubated untreated S. mutans cells, cells coated with whole human saliva, cells treated with HCl (pH 2.0), and saliva-coated and acid-treated cells in mice was investigated. Saliva and serum samples were assayed by enzyme linked immunosorbent assay for immunoglobulin A (IgA) and IgG antibodies, respectively, against the untreated or treated S. mutans cells. In general, the levels of salivary IgA and serum IgG antibodies to the antigen against which the mice were immunized were significantly higher (P  0.05). In addition, human saliva and serum samples from 12 subjects were assayed for naturally occurring antibody against the untreated or treated S. mutans cells. In every case, significantly higher reactivity was directed against the saliva-coated and acid-treated cells followed by the saliva-coated S. mutans. These results provide evidence for the altered immunogenicity of swallowed S. mutans in humans by coating native S. mutans antigens with salivary components and/or denaturing surface S. mutans antigens in the acidic environment of the stomach, which would lead to an immune response to modified S. mutans determinants and not to native S. mutans antigens.