Nerve growth factor (NGF) has protective effects against striatal excitotoxic injury in the adult brain. To begin to define the mechanism of NGF-mediated sparing, we sought to determine the effects of biologically delivered NGF on the degree of neuronal stress and the development of excitotoxic lesions in the rat striatum. Immortalized fibroblasts genetically altered to secrete NGF (NGF[+]) or control fibroblasts (NGF[-]) were stereotactically implanted near the striatum 7 d before striatal infusion of an NMDA-receptor agonist. Two days after excitotoxin infusion, the volume of neuronal loss was reduced by 34% (p < 0.001) in the NGF[+] group when compared to the NGF[-] group; however, there was no difference in the volume of 72 kD heat shock protein (HSP72) immunoreactivity expressed in the two groups after 2 d. The final volumes of neuronal loss at 10 d were significantly greater than seen at 2 d, with the volume of neuronal loss in the NGF[+] group reduced by 20% (p < 0.004) when compared to the NGF[-] group. Interestingly, the volume of neuronal loss at 10 d in the NGF[-] group, but not the NGF[+] group, closely approximated the HSP72 immunoreactive volumes seen at 2 d. These results suggest that the cell stress marker, HSP72, is predictive of neuronal loss after striatal excitotoxic insult and while NGF treatment does not alter the overall HSP72 response, it significantly reduces subsequent neuronal loss. We conclude that NGF-mediated neuroprotective mechanisms alter neuronal response to injury without affecting the primary cell stress response to NMDA-receptor activation.