Bacterial meningitis is accompanied by an acute inflammatory response which may be exacerbated by antibiotic treatment and subsequent killing of bacteria. Bacterial cell products induce the release of cytokines including TNF, which contribute to the inflammatory process. Alpha-1-acid glycoprotein (AAG), an acute phase reactant, is elevated during inflammation. To test whether AAG has anti-inflammatory activity we examined its effect on lipopolysaccharide-stimulated human peripheral blood mononuclear cells. Treatment of the cells with AAG in vitro resulted in reduced TNF production. To test the effects of the molecule in vivo, AAG was administered intrathecally to rabbits with Haemophilus influenzae B lysate induced meningitis. Human AAG reduced TNF production and leukocytosis in the cerebrospinal fluid. Histopathology of the leptomeninges showed markedly attenuated inflammation. These results indicate that AAG can reduce inflammation in rabbits with experimental meningitis and that the effect may be directly on TNF production by stimulated mononuclear leukocytes.