Neurodegenerative effects of 1-methyl-4-phenylpyridinium (MPP+), the main metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) include enhancement of lipid peroxidation in the striatum of mice, associated to overproduction of free radicals. Copper acts as a prosthetic group of several copper-dependent antioxidant enzymes, and we previously showed the neuroprotective effect of CuSO4 pretreatment against the MPP+-induced neurotoxicity. In those studies, acute administration of CuSO4 (2.5 mg/kg) blocked MPP+-induced striatal lipid peroxidation, suggesting the activation of Cu-dependent proteins that defend neurons from damage elicited by free radicals. In the present study, we evaluated the activity of superoxide dismutase in mice pretreated with CuSO4 16 h or 24 h prior to MPP+ administration. Copper administration produced a specific and significant increase in manganese superoxide dismutase activity in both the CuSO4/saline (fivefold increase) and the CuSO4/MPP+ groups of animals (sevenfold increase). The Na2SO4/MPP+ group showed a twofold increase in manganese superoxide dismutase activity versus control levels. The results suggest that the load of copper activating manganese-dependent superoxide dismutase could be responsible for neuroprotection against the MPP+ insult.