Current methods of immunosuppression for the purposes of allowing solid organ transplantation in humans are broadly inhibitory and thus are associated with an increased risk of opportunistic infections and neoplasia. We have shown previously that a selective blockade of CD40–CD154 interactions during heart transplantation in cynomolgus macaques significantly delays immune-mediated graft injury. Here, we determined the effect of anti-CD154 mAb therapy on primate serologic responses to immunization with influenza virus hemagglutinin (HA), a T-cell-dependent Ag. We found that CD154 blockade attenuated primary and secondary serum Ab responses of IgM and IgG isotypes to influenza, even when anti-CD154 treatment was discontinued prior to reimmunization. These findings show that in primates CD40–CD154 interactions are necessary for both primary and secondary Ab responses to viral Ags. Furthermore, the data suggest that viral Ag stimulation of primates in the absence of CD154 stimulation may have a tolerizing effect on that Ag.