In this report female and male CD-1 mice were treated with a neurotoxic regimen of methamphetamine (MA) to compare gender differences in striatal dopamine depletion and concordant changes in mRNA markers of the transforming growth factor-β injury response associated with neurodegeneration. Striatal dopamine concentrations of MA-treated female mice were less depleted and significantly greater than that of identically treated males. Associated with this gender difference in striatal dopamine depletion were significantly decreased mRNA levels of plasminogen activator inhibitor-1 and a trend for increased (p = 0.06) mRNA levels of glial fibrillary acidic protein within females. No statistically significant differences between MA-treated female and male mice were obtained in mRNA levels for transforming growth factor-β, transforming growth factor-β type 2 receptor, activin-like kinase-5 or fibronectin. These data demonstrate the presence of changes in two specific molecular markers of the transforming growth factor-β injury response which are in accordance with gender differences in MA-induced striatal dopamine depletion. The results suggest that the neuroprotective advantage displayed by females may in part be related to reductions in the transforming growth factor-β injury response as indicated by decreased mRNA plasminogen activator inhibitor-1 and an increased response of reactive astrocytes which promote neuronal survival as indicated by augmented glial fibrillary acidic protein mRNA levels.