Natalizumab (NAT) was the first disease modifying therapy used for the treatment of relapsing-remitting multiple sclerosis (MS) that was designed with a specific mechanism of action that targets an important step of the MS immunopathology, directly blocking the T lymphocyte intrusion in the central nervous system. Initially, it was considered that NAT carried no biological effects on the peripheral immune response. The purpose of our study was to assess the effects of NAT on the peripheral pro and anti-inflammatory cytokines and to reveal possible correlations between them and the clinical activity of the disease. We noticed a significant decrease in interleukin (IL)-17, tumor necrosis factor-alpha (TNF-α) and IL-31 serum levels in treated patients. The lack of relapses during the study was associated with low baseline IL-17 level. The patients that had an increase in the disability score during the study had significantly lower IL-17 and higher IL-1β baseline levels. IL-17 can be used as a biomarker for disease activity but also for progression assessment in NAT treated patients. NAT has a far more complex mechanism compared to what was initially believed, besides modulating lymphocyte trafficking through the blood-brain barrier, it also changes the peripheral levels of pro and anti-inflammatory cytokines in MS patients.