Harvard caries-resistant rats (CR) monoassociated with cariogenic Streptococcus faecalis (SF) for 150 days developed early high levels of specific SF serum agglutinins, moderate levels of salivary antibody, and little or no caries activity. Harvard caries-susceptible (CS) SF-monoassociated rats developed serum antibody more slowly and never reached the titers of the CR group. Little or no salivary agglutinin was found, and extensive caries developed. Second-generation monoassociated CR rats (CR-2) born to SF-monoassociated CR parents showed an immune response and caries activity more nearly resembling those of the CS rat than those of their CR parent. The CR rat appeared to be a high responder and the CS rat, a low responder to viable antigen on the mucous surfaces in both serum and salivary antibody production. Immunization by parenteral injection of killed SF cells produced equally high serum titers in both CR and CS strain rats, but failed to increase salivary agglutinin titers in any group or to protect against caries. These data suggest that there may be an immunologic basis for genetic differences in caries susceptibility between CR and CS Harvard rat strains and that this difference has been modified by some factor in the environment of the CR-2 rats.