Heat-killed Streptococcus mutans was administered orally in two periods of 1 week to six subjects in an attempt to affect the salivary immunoglobulin A (IgA) response to this bacterium. Enzyme-linked immunosorbent assays were used to detect specific IgA antibody activity, and an immunofluorescent assay was used for measurement of total IgA in parotid saliva. The salivary IgA response to S. mutans was compared with that against a noncross-reacting antigen preparation from Escherichia coli and with antibody responses in five sham-immunized subjects. No change in salivary IgA response to S. mutans was observed after oral administration of this organism. Significantly less streptomycin-resistant S. mutans could be recovered from the six test subjects than from the five controls after the first of two challenges with streptomycin-resistant microorganisms. At the day of the first challenge, a significantly higher IgA antibody response to all tested antigens was observed in the test group than in the control group. The data show that this difference was not related to the oral administration of S. mutans but rather was an occasional finding. The coincidence of a rapid elimination of the challenge strain and a high IgA antibody response to S. mutans supports the concept that salivary IgA antibodies could have a biological significance in the human defense against cariogenic microorganisms.