Cornu Bubali (water buffalo horn, WBH) is an animal-derived product which is widely used in Traditional Chinese Medicine (TCM) for dispelling heat, relieving convulsions and cooling blood. The purpose of this study was to investigate the antipyretic activity of WBH aqueous extract and its potential mechanism. Two hyperthermia models, yeast-induced (infectious) and skimmed milk-induced (noninfectious) hyperthermia were employed to evaluate the antipyretic effect and the results showed that rectal temperature of hyperthermia animals was decreased significantly after oral administration of WBH extract. The production of tumor necrosis factor-alpha (TNF-alpha)-induced prostaglandin E(2) (PGE(2)) in rat cerebral microvascular endothelial cells (rCMECs) was inhibited by WBH extract in the concentrations of 10 microg/ml and 100 microg/ml. The WBH extract protected rCMECs survival from hydrogen peroxide (H(2)O(2))-induced toxicity and inhibited the H(2)O(2)-induced leakage of lactate dehydrogenase (LDH) enzyme release at a dose ranging from 5 microg/ml to 100 microg/ml. It could also increase the superoxide dismutase (SOD) and catalase (CAT) enzyme activities. The results suggest that Cornu Bubali exhibits antipyretic activity on both infectious and noninfectious hyperthermia. The antipyretic activity of WBH may be due to the effects on enhancing antioxidation enzyme activities, decreasing PGE(2) production, and protecting the rCMECs against H(2)O(2)-induced injury.