In rodents, the Plaque Assay, T-dependent antibody response to sheep erythrocytes (SRBC), has been reported to be a sensitive and predictive functional immune assay for detecting immunomodulatory compounds. However, various laboratories have chosen to use ELISA-based assays for evaluating the primary immune response in rodents. The ELISA-based assays offer several advantages over the Plaque Assay, which make them attractive for use in immunotoxicological evaluations. Among the most popular antigens used in the ELISA-based assays are SRBC and more recently KLH. While the Plaque Assay and the ELISA-based assays are both capable of evaluating the humoral immune response, they are measuring different endpoints. The Plaque Assay focuses primarily on splenic effects. ELISA-based assays, which use serum from immunized animals, are holistic in nature in that these assays measure effects of antibody production on the spleen, lymph nodes, and bone marrow. Depending on the drug or compound evaluated, different effects and degrees of sensitivity can be seen with the Plaque Assay and ELISA-based assays. One recent finding is that the sensitizing dose of KLH used in the KLH ELISA differentially affects the responses observed in rodents. Even within the same species, different strains of mice and rats produce different magnitudes of responses to the same sensitizing dose. A key component of this discussion focuses on the sensitivity of the Plaque Assay as compared to KLH ELISA-based assays. These assays were evaluated by comparing the response obtained following administration of several known immunosuppressive agents, including cyclophosphamide, azathioprine, cyclosporine A and dexamethasone. The effects on the primary IgM immune response in the B(6)C(3)F(1) mice, the primary immunotoxicological rodents used by National Toxicology Program, and in the Sprague-Dawley rat, the primary rodent models used by industry are addressed.