Copper (Cu) is a transition element essential for life whose metabolism is implicated in the pathogenesis of neurodegenerative diseases. At the moment, limited and conflicted work has been done on the possible role of this metal in Multiple Sclerosis (MS). In this work we evaluated the Cu levels and ceruloplasmin (Cp) activity in serum and cerebrospinal fluid (CSF) of MS patients. Cp is the major plasmatic Cu-carrying protein, whose ferroxidase activity is associated with progressive neurodegeneration. Results showed that serum Cu levels were lower in MS patients than in controls, while we found upper levels of this metal in patients's CSF. Furthermore, both serum and CSF Cp activity were lower in MS patients than in controls. These data suggest that an impairment of Cu metabolism could occur in MS patients altering expression and activity of Cu binding proteins involved in the energetic shift also in CD4⁺ lymphocytes, the cellular population implicated in autoimmune response typical of MS. Immunoblot analysis revealed an upregulation of proteins involved in glycolysis (Glut-1, HIF-1, PrP), a downregulation of proteins implicated in oxidative phosphorylation (SCO1-2) and a downregulated expression of Cu transporters (ATP7A, CTR1) in CD4⁺ T-cells of MS patients than controls. These preliminary results let us speculate that CD4⁺ lymphocytes of patients affected by MS may undergo a metabolic shift, probably due to an alteration of Cu homeostasis.