Consistent with known cytoprotective effects, mild heat stress reduced the vulnerability of cultured cortical neurons to glutamate-induced cell death. However, this neuroprotective effect occurred without expression of the inducible heat stress protein, hsp70, as detected by immunocytochemistry, immunoblotting, or metabolic labeling. Present data suggest that the anti-excitotoxic effect of mild heat stress is mediated outside of the traditional hsp70 mechanism.