Crosstalk between complement and Toll-like receptors (TLRs) coordinates innate immunity. We report a previously unknown immune subversion mechanism involving microbial exploitation of communication between complement and TLRs. Porphyromonas gingivalis, a major oral and systemic pathogen with complement C5 convertase-like activity, synergizes with C5a (fragment of complement protein C5) to increase cyclic adenosine monophosphate (cAMP) concentrations, resulting in suppression of macrophage immune function and enhanced pathogen survival in vitro and in vivo. This synergy required TLR2 signaling, a pertussis toxin- and thapsigargin-sensitive C5a receptor pathway, with protein kinase A and glycogen synthase kinase-3beta as downstream effectors. Antagonistic blockade of the C5a receptor abrogated this evasive strategy and may thus have important therapeutic implications for periodontitis and atherosclerosis, diseases in which P. gingivalis is implicated. This first demonstration of complement-TLR crosstalk for immunosuppressive cAMP signaling indicates that pathogens may not simply undermine complement or TLRs (or both) as separate entities, but may also exploit their crosstalk pathways.