The effects of an ether extract of fetal calf serum (EE-FCS) on glutamate-induced cytotoxicity were examined using primary cultures of rat cortical neurons. The simultaneous addition of EE-FCS and glutamate reduced glutamate cytotoxicity in a concentration-dependent manner. EE-FCS also reduced the cytotoxicity induced by S-nitrosocysteine, a nitric oxide (NO) donor. The findings indicate that EE-FCS contains lipid-soluble, non-peptide substances with neuroprotective actions against NO-mediated glutamate neurotoxicity.