This report is part of a 2-year study assessing the functional effect of Brain-Derived Neurotrophic Factor (BDNF) and its Val66Met polymorphism on a selected population of Relapsing-Remitting Multiple Sclerosis (RRMS) patients from Southern Italy. For this purpose, we measured the peripheral BDNF expression in RRMS patients compared to healthy controls. The influence of concomitant IFNbeta therapy was also evaluated. Thirty-six inactive RRMS patients and 37 healthy controls were genotyped for BDNF Val66Met, and total RNA was extracted at time-points 0-24 months. The BDNF level was quantified by ABI Prism 7900 HT Sequence Detection System, and its relative expression was calculated by the comparative method of 2(-DeltaDeltaCt). At baseline and after 24 months, the BDNF levels of RRMS patients resulted significantly higher than controls (p=0.001), independently of the concomitant IFNbeta treatment; no correlations were found with the investigated clinical and MRI features of MS. Otherwise, carriers of the Met-allele showed significantly higher levels of BDNF in RRMS patients than healthy controls (p=0.005). These data was replicated after a 24-month interval. The present study confirms the increased levels of peripheral BDNF levels in RRMS, even during the inactive phase of the disease. Although with caution due to the small sample size, it also underscores the potential role of the Val66Met polymorphism on the peripheral BDNF expression in RRMS. Functional studies are needed to better clarify this issue.