Evidence suggests that tumor necrosis factor alpha (TNF) is a leading cause of dopaminergic neuronal cell death. TNF also, however, has neuroprotective effects. Thus, TNF might have a dual role following injury: immediate release after injury is protective, whereas chronic increases are detrimental. In the present study, 6-hydroxydopamine was used to lesion the dorsal striatum in male Fisher 344 rats at 2 different time points. Group 1 received a daily injection of TNFalpha antisense oligodeoxyribonucleotide (ODN) or control on days 1 through 7 post-lesion. Group 2 received a daily injection of TNF antisense ODN or control on days 5 through 15 post-lesion. Rats were killed on the day following the last injection of TNF antisense ODN. Injection of TNF antisense ODN on days 1 through 7 increased the area of the tyrosine-hydroxylase-negative zone ipsilateral to the injection when compared to controls. In contrast, when inhibition of TNF was delayed, the area of tyrosine hydroxylase loss was significantly reduced. These findings suggest that TNF release is neuroprotective in the early stages of injury but becomes neurotoxic when chronically induced.