Natural interferon‐producing cells (IPC) secrete type I IFN (IFN‐α and ‐β) in response to influenza virus. This process is independent of viral replication and is mediated by Toll‐like receptor 7 (TLR7), which recognizes single‐stranded RNA (ssRNA). DC also express TLR7 but its function in DC response to influenza virus is unknown. To address this, we compared the DC and IPC responses to influenza virus and ssRNA oligoribonucleotides (ORN) that activate TLR7. When stimulated by ORN in vitro and in vivo, DC matured and produced inflammatory cytokines but not IFN‐α. DC did secrete IFN‐α in response to influenza virus. However, this response was independent of TLR7 signaling and required viral replication but not dsRNA‐activated protein kinase (PKR). We conclude that DC and IPC are hard‐wired to secrete IFN‐α via different pathways, reflecting their complementary but distinct roles in anti‐viral immunity.