1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective dopaminergic neurotoxin affecting the nigrostriatal system in a variety of species including, rodents, nonhuman primates and humans. There exists, however, a great deal of variability in the sensitivity of different species to the effects of MPTP. The present study was designed to determine whether a significant difference in gender susceptibility to the toxin in CD-1 mice might also exist. A dosing regiment of 30 mg/kg MPTP once a day for 3 days (90 mg/kg total dose) in 4-month-old male and female CD-1 mice led to a significant depletion of striatal dopamine in both sexes. Two way ANOVA analysis of a time-course generated by measuring striatal dopamine at 4, 12 and 24 h after each dose of MPTP revealed that the initial dopamine reduction is significantly greater in male CD-1 mice (P < 0.001). Further, dopamine levels were reduced to a greater extent in male mice 5 days after the last dose (31% vs. 59% of control; P < 0.02). HPLC analysis using fluorescence detection revealed no difference in the striatal nor the cerebellar levels of MPP+ between the two sexes, however, accumulation of larger amounts of MPP+ was observed in the livers of the female mice. These findings suggest that, while female CD-1 mice are more resistant to the dopamine-depleting effects of MPTP, this gender difference is not due to decreased or accumulation of striatal MPP+.