The flower buds of Tussilago farfara L. (Compositae) have been traditionally used in Oriental medicine for the treatment of bronchitis and asthma. The extract of T. farfara was reported to exhibit antiinflammatory actions by inhibiting arachidonic acid metabolism and nitric oxide (NO) production in lipopolysaccharide-activated macrophages. In the present study, we investigated the effects of the ethyl acetate (EA) fraction on various types of neuronal cell damage induced in primary cultured rat cortical cells. Its antioxidant activities were also evaluated by cell-free bioassays. We found that the EA fraction potently inhibited the neuronal damage induced by arachidonic acid. We also found that it significantly attenuated the neuronal damage induced by spermine NONOate, a stable NO generator. In addition, it inhibited the A(beta(25-35))-induced neurotoxicity and glutamate- or N-methyl-D-aspartic acid-induced excitotoxicity. It was found that the oxidative neuronal damage induced by H2O2, xanthine/xanthine oxidase, or Fe(2+)/ascorbic acid was also inhibited by the EA fraction. Furthermore, it was shown to inhibit lipid peroxidation initiated by Fe(2+)/ascorbic acid in rat brain homogenates, and scavenge DPPH radicals. This is the first demonstration of neuroprotective and antioxidant effects of T. farfara. Although complex mechanisms may be involved in the neuroprotective actions, T. farfara may be useful for the management of neurodegenerative disorders associated with inflammation, A(beta), excitotoxicity, and/or oxidative stress.