Type I IFN (IFN-αβ) is induced rapidly by infection and plays a key role in innate antiviral defense. IFN-αβ also exerts stimulatory effects on the adaptive immune system and has been shown to enhance Ab and T cell responses. We have investigated the importance of B and T cells as direct targets of IFN-αβ during IFN-α-mediated augmentation of the Ab response against a soluble protein Ag. Strikingly, the ability of IFN-α to stimulate the Ab response and induce isotype switching was markedly reduced in mice in which B cells were selectively deficient for the IFN-αβR. Moreover, IFN-α-mediated enhancement of the Ab response was also greatly impaired in mice in which T cells were selectively IFN-αβR-deficient. These results indicate that IFN-αβR signaling in both B and T cells plays an important role in the stimulation of Ab responses by IFN-αβ.