Bacillus anthracis is surrounded by an antiphagocytic polypeptide capsule composed of poly γ-d-glutamic acid (γDPGA). γDPGA has been identified recently as a potential target for vaccine development. Studies of the role of γDPGA in disease have been hampered by the poor Ab response to this antigen and the lack of immunochemical reagents. As a consequence, neither the extent of γDPGA production during anthrax nor the protective activity of γDPGA Abs in inhalation anthrax are known. Here we report production of IgG Abs to γDPGA in mice following an immunization regimen using γDPGA in combination with agonist mAbs to CD40. mAbs were produced that are specific for γDPGA. Passive immunization with γDPGA mAbs protected >90% of mice in a pulmonary model of anthrax that was lethal in control mice (P < 0.0001). Use of γDPGA mAb in an antigen detection immunoassay found that the appearance of γDPGA in serum coincided with the emergence of bacteremia. These studies identify CD40 stimulation as a means for production of Ab and generation of mAbs against a weakly immunogenic antigen and demonstrate that the capsule is an effective target for immunoprotection and for antigen detection in the diagnosis of anthrax.