Proteome analysis of body fluids is a powerful tool to identify biomarkers of neurological disorders. Multiple sclerosis (MScl) is a chronic disabling disorder of central nervous system (CNS) and is regarded as an autoimmune disease to myelin components. Clinical subtypes of MScl differ in course, prognosis and response to available therapy. There is evidence of a different pattern of CNS lesions in subtypes, suggesting different immunological mechanisms are relevant in inflammatory demyelination. In order to elucidate proteome signatures, we used two-dimensional differential gel electrophoresis (2D-DIGE) to compare the protein expression profile in serum of different clinical subtypes of MScl patients and of healthy volunteers, resp. controls. Significant expression differences were detected by 2D-DIGE for 241 serum proteins, and transthyretin, zinc-alpha-2-glycoprotein, alpha-1-antitrypsin, immunoglobulin and complement factors (C4, C6 and C8) were identified as potential disease signatures for MScl patients. Three highly-expressed proteins were selected for further evaluation in individual patients by independent immunoassays, and the up-regulation of transthyretin, zinc alpha-2-glycoprotein and immunoglobulin kappa light chain was validated in sera of relapsing-remitting (CIS and RRMScl) patients, when compared to healthy donors. To present significant expression differences in PPMScl, analysis with a larger patient population is required.