Activation of the innate immune system, even by relatively innocuous stimuli, stimulates the release of cytokines (e.g. TNF) that can injure or kill the host. To maintain homeostasis, mammals have evolved a counter-regulatory response that suppresses the development of excessively robust inflammation. Fetuin, a 66-kD negative acute phase glycoprotein, was first identified in 1944. We recently discovered an anti-inflammatory role for fetuin, because it suppressed the release of TNF from lipopolysaccharide- (LPS) stimulated macrophages. Here the anti-inflammatory effects of fetuin were studied in vivo in an LPS-independent model of acute inflammation caused by administration of carrageenan. Administration of fetuin (5-500 mg/kg intraperitoneally) dose-dependently attenuated the development of paw edema as compared to either asialofetuin (500 mg/kg) or bovine albumin (500 mg/kg). TNF production in the carrageenan-injected paws was significantly inhibited by administration of fetuin (586+/-98 pg TNF/paw) as compared to either asialofetuin (1018+/-186 pg TNF/paw) or saline (1,005+/-172 pg TNF/paw). When specific anti-fetuin IgG was administered into the paw prior to the application of carrageenan, the development of edema formation was significantly increased as compared to irrelevant IgG, indicating that endogenous fetuin normally attenuates the inflammatory response. These results now reveal a previously unrecognized anti-inflammatory role of fetuin in counter-regulating the innate immune response, and suggest that it may be possible to use fetuin as an experimental anti-inflammatory agent.