Estrogen acts as a neuroprotectant of the nigrostriatal dopaminergic system when given chronically to female mice prior to Methamphetamine (MA) insult. In this report, we tested the acute effects of Estradiol Benzoate (EB-10 microg in Oil) in ovariectomized CD-1 mice to function as a neuroprotectant when administered prior to (Experiment 1) or after (Experiment 2) MA treatment. Striatal dopamine (DA) concentrations and DOPAC/DA ratios were measured to assess the neuroprotective effects of EB. In Experiment 1, we observed that EB exerted a neuroprotective effect upon striatal dopamine concentrations when administered at 24 and 12, but not at 0.5, hours prior to MA injection and upon DOPAC/DA ratios when administered at 24, 12 and 0.5 hours prior to MA. In Experiment 2, no evidence for estrogen to protect the striatum from MA insult was obtained when EB was administered at 15, 30, 60 or 120 minutes after MA. These results show that EB can act as a modulator of MA-induced nigrostriatal dopaminergic neurotoxicity suggestive of a neuroprotectant, when administered within 0.5 hour of MA insult as assessed by measures of DOPAC/DA, but fails to prevent depletion of DA when given after MA insult. The data suggest that estrogen may exert this rapid neuroprotective effect through a non-genomic mechanism.