Synthesis of complement components is part of the acute-phase response. Interleukin-6 (IL-6) is a critical mediator of the acute-phase response during infections and injuries. Plasma levels of C3a and IL-6 have been proposed as prognostic indicators in sepsis and trauma. The effects of C3a and C3a(des)Arg on IL-6 gene expression and protein production in human peripheral blood mononuclear cells (PBMC) were investigated. Neither C3a nor C3a(des)Arg alone induced detectable IL-6 protein or mRNA levels. However, C3a and C3a(des)Arg affected endotoxin-induced IL-6 synthesis in a dose-dependent manner. In nonadherent PBMC, C3a or C3a(des)Arg suppressed, while in adherent PBMC, C3a or C3a(des)Arg enhanced IL-6 protein and mRNA levels. These results suggest that C3a and C3a(des)Arg may provide a control mechanism of acute-phase responses by enhancing IL-6 synthesis in adherent monocytes at local inflammatory sites and by inhibiting IL-6 synthesis in circulating monocytes.