The presence of autoantibodies in multiple sclerosis (MuS) is well known, but their target antigens have not been clearly identified. In the present study, IgG autoreactivity to neural antigens of normal human white matter separated by bi-dimensional electrophoresis was assessed in serum and cerebro-spinal fluid (CSF) of 18 MuS and 20 control patients. Broad IgG autoreactivity was detected by 2D-immunoblotting in all cases to neural antigens, most of which have been identified by mass spectrometry. The comparative analysis of MuS and non-MuS reactive spots showed that a restricted number of neural protein isoforms was specifically recognized by MuS IgG. Almost all MuS patients had CSF IgG directed to isoforms of one of the oligodendroglial molecules transketolase (TK), cyclic nucleotide phosphodiesterase type I (CNPase I), collapsin response mediator protein 2 and tubulin beta4. Interestingly, 50% of MuS IgG recognized TK, which was mostly localized on oligodendrocytes in human white matter from normal and MS samples. IgG autoreactivity to cytoskeletal proteins (radixin, sirtuin 2 and actin interacting protein 1) was prevalent in secondary progressive MuS patients. Among the proteins recognized by serum IgG, almost all MuS patients specifically recognized a restricted number of neuronal/cytoskeletal proteins, while CNPase I was the oligodendroglial antigen most frequently recognized (44%) by MuS seric IgG. Our immunomic approach shed new light on the autoimmune repertoire present in MuS patients revealing novel oligodendroglial and/or neuronal putative autoantigens, with potential important pathogenic and diagnostic implications.