This cross-sectional study investigated with two-dimensional gel electrophoresis coupled to MALDI-TOF and MRI the relationship between PBMCs protein expression profile and whole-brain atrophy in 16 unselected RR-MS IFN-treated patients compared with 6 RR IFN-untreated and 12 matched healthy control subjects. Grey/white matter fraction, T1/T2 lesion load and clinical variables were considered too.Twenty six proteins showed significant differential expression among RR IFN-treated patients and control samples. Four of these (IN35, GANAB, PP1B, SEPT2) resulted correlated with clinical and MRI findings in RR IFN-treated MS patients.Future clinical applications remain to be validated by other techniques and confirmed by a larger study.