Human C1q displayed a dose-dependent protection of gonococcal cells (GC) from the bactericidal effect of newborn rat serum. All rat pups injected with C1q-preincubated GC developed bacteremia, while none of the animals injected with GC only were infected. After clearance of bacteremia at day 6, live GC could still be recovered from tested organs, including the liver. Preincubation of GC with higher concentrations of C1q was associated with increased morbidity. In contrast to human serum as a source of C1q, rat, rabbit, and mouse sera did not increase the in vivo virulence of Neisseria gonorrhoeae. C1q-deficient human serum, heat-inactivated C1q or human serum, type IV collagen, and complement C3 were inefficient in inducing infection. Experimental infection by C1q-preincubated GC was inhibited by anti-C1q antibodies in a dose-dependent fashion, demonstrating a causal effect of C1q function. This report demonstrates the novel finding that human C1q, a component of the human immune system with a general function for elimination of infection, may increase GC virulence and result in the development of disseminated infection in a nonhuman host.