Capnocytophaga canimorsus is a commensal bacterium from the canine oral flora, which can cause septicemia or meningitis in humans upon bite wound infections. C. canimorsus 5 (Cc5), a strain isolated from a patient with fatal septicemia, was used to investigate the interaction between C. canimorsus and J774.1 mouse macrophages. J774.1 cells infected at high multiplicity with Cc5 did not phagocytose nor kill Cc5 within 120 min of infection, unless the bacteria were opsonized with specific antibodies. Opsonization with complement, however, did not increase phagocytosis. Moreover, infection of J774.1 cells with live Cc5 led to the release of a soluble factor, which interfered with the ability of macrophages to kill other phagocytosed bacteria. These results provide an example of how C. canimorsus neutralizes the innate immune system.