Influenza is still one of the major plagues worldwide. The statistical likeliness of a new pandemic outbreak highlights the urgent need for new and amply available antiviral drugs. We and others have shown that influenza virus misuses the cellular IKK/NF-kappaB signalling pathway for efficient replication suggesting that this module may be a suitable target for antiviral intervention. Here we examined acetylsalicylic acid (ASA), also known as aspirin, a widely used drug with a well-known capacity to inhibit NF-kappaB. We show that the drug efficiently blocks influenza virus replication in vitro and in vivo in a mechanism involving impaired expression of proapoptotic factors, subsequent inhibition of caspase activation as well as block of caspase-mediated nuclear export of viral ribonucleoproteins. As ASA showed no toxic side-effects or the tendency to induce resistant virus variants, existing salicylate-based aerosolic drugs may be suitable as anti-influenza agents. This is the first demonstration that specific targeting of a cellular factor is a suitable approach for anti-influenza virus intervention.