Rapidly developing Ab responses to influenza virus provide immune protection even during a primary infection. How these early B cell responses are regulated is incompletely understood. In this study, we show that the first direct stimulatory signal for local respiratory tract B cells during influenza virus infection is provided through the type I IFNR. IFNR-mediated signals were responsible for the influenza infection-induced local but not systemic up-regulation of CD69 and CD86 on virtually all lymph node B cells and for induction of a family of IFN-regulated genes within 48 h of infection. These direct IFNR-mediated signals were shown to affect both the magnitude and quality of the local virus-specific Ab response. Thus, ligand (s) of the type I IFNR are direct nonredundant early innate signals that regulate local antiviral B cell responses.