Oxidative stress markers have been found in nervous and peripheral tissues of familial and sporadic amyotrophic lateral sclerosis patients. Here, we evaluated the activity of some antioxidant enzymes glutathione peroxidase, glutathione reductase and Cu-Zn superoxide dismutase in erythrocyte, the marker of non-enzymatic antioxidant response (total antioxidant status), as well as plasma reactive oxygen species, at the enrolment and during disease progression in 88 patients affected by the sporadic form of amyotrophic lateral sclerosis. Our study has been performed along 72 months by grouping the patients according to the ALS functional rating score or rate of disease progression. Our results showed a significant impairment of erythrocytes glutathione peroxidase activity in all groups of patients that remained low during disease time course. SOD1 activity significantly decreased along disease course in subjects with a more impaired functional status. A decreasing activity of all assayed enzymes was found in patients who have a faster disease progression rate. By this work we have the evidence that different ALS phenotypes present with different profile of enzymatic and non-enzymatic antioxidant response.