There is increasing evidence that health effects of toxic metals, including methylmercury (MeHg), differ in prevalence or are manifested differently in men and women. The present study was aimed at investigating the potential differential susceptibility of male and female Swiss mice against MeHg-induced neurotoxicity, which was evaluated by biochemical (cerebellar oxidative stress-related parameters) and behavioral (locomotor activity and motor performance) variables. We also aimed to evaluate the potential protective effects of 17β-estradiol against such toxicity in MeHg-exposed male animals. MeHg exposure (40mg/L, diluted in tap water, during 2 weeks) decreased locomotor activity and motor performance in both male and female animals, but such phenomena were higher in males. 17β-estradiol co-treatment (10μg/animal, in alternate days) prevented MeHg-induced locomotor deficits in males. MeHg exposure caused a significant increase (60%) in cerebellar lipid peroxidation in male mice, but did not in females. In close agreement, MeHg exposure decreased (43%) cerebellar glutathione peroxidase activity in males, but did not in females. These events were prevented by 17β-estradiol administration. Cerebellar GR activity was increased (25%) in MeHg-exposed males and such event was partially prevented by 17β-estradiol administration. These results indicate that the low susceptibility of female mice to the neurotoxicity elicited by MeHg is linked to neuroprotective effects of sex steroids, which appear to modulate the activities of glutathione-related enzymes. Our experimental observation corroborates previous epidemiological studies showing the greater developmental effects in male than in female humans exposed to MeHg.