The coagulation system is important for immune defence in 'living fossils', such as the horseshoe crab, but it is not clear whether it contributes to immunity in higher organisms. This study shows that human coagulation factor X can bind to human adenovirus C (HAdv-C), thereby forming a complex that serves as a pathogen-associated molecular pattern for the activation of innate immune pathways. A mutant form of HAdv-C that could not complex with factor X did not induce the NF-κB-dependent pro-inflammatory responses that are normally associated with HAdv-C infection. Further analyses showed that Toll-like receptor 4- and TRAF6-mediated signalling are also required for a full-scale inflammatory response to HAdv-C.