The effects of immunization with Streptococcus mutans on the development of caries and the immune responses were investigated in 37 young rhesus monkeys (Macaca mulatta) during a period of up to 33 months. The monkeys were supplied a human type of carbohydrate-rich diet that contained about 15% sucrose. The monkeys were separated into seven groups, and the effects of two whole cell vaccines and an extracellular culture extract of S mutans in Freund's incomplete adjuvant were compared with a vaccine of a noncariogenic Streptococcus CHT, the adjuvant alone, and a sham immunized group. Sequential analysis of complement fixing, hemagglutinating and precipitating antibodies to the cell wall, and extracellular culture extract have shown that a significant reduction in smooth surface and fissure caries resulted from immunization with the S mutans vaccines, if antibodies reached an optimum level before caries development started. Protection was not elicited by the culture extract of S mutans or the noncariogenic Streptococcus CHT vaccines. A recently developed bacteriological sampling technique of crevicular fluid, plaque, and saliva showed that caries reduction in immunized animals was associated with a significantly decreased percentage of S mutans in crevicular fluid. Immunochemical studies showed IgG and IgM classes of antibodies in serum and secretory IgA antibodies in saliva, but it appears that reduction in caries was best associated with serum IgG antibodies to the culture extract of S mutans. The humoral and cellular mechanisms involved in the immunologic control of caries are discussed in terms of a central afferent mechanism required for antigen processing and cellular proliferation, and two peripheral effector mechanisms that function in the crevicular and salivary domains.