The guinea pig serves as a useful animal model for a number of human diseases and has played an important role during development and testing of experimental vaccines and disease therapies. However, the availability of reagents to examine the immunological response in this species is very limited. Monoclonal antibodies (mAb) specific for cell surface proteins or products of immune cells have been useful tools for characterizing and quantifying immune responses in humans and in murine models of human disease, but very few similar reagents are available for characterizing and manipulating the immune response of guinea pigs. A rat IgG2a mAb specific for guinea pig CD4 has previously been described and was shown to inhibit T cell proliferation, but was inefficient at depleting CD4+ T cells in vivo. We hypothesized that the in vivo CD4+ T cell depletion function of this mAb could be improved by expression of the rat IgG2b heavy chain. We show that the purified mAb from an IgG2b class-switch variant, but not the parental IgG2a mAb, significantly depleted CD4+ T cells from secondary lymphoid tissue of guinea pigs. Further, treatment of guinea pigs with the IgG2b mAb at 2.0 mg/kg resulted in depletion of CD4+ T cells from peripheral blood and spleen. The use of this modified antibody to specifically alter the immune response of guinea pigs should prove useful in a number of guinea pig infectious disease models.