Multiple Sclerosis (MS) is an immune-mediated and neurodegenerative disease of central nervous system. Relapsing-remitting (RR)-MS occurring with acute attacks and remissions, is the most common clinical type of MS. There are different strategies applied in first-line treatment of RR-MS patients such as interferon-beta (IFN-beta) and glatiramer acetate. In this study, activating and inhibitory receptor expressions and interleukin (IL)-22 levels of NK cells were investigated in RR-MS patients with or without IFN-beta therapy. Activating receptor expression and IL-22 levels of NK cells were increased in RR-MS patients under IFN-beta therapy. Elevated NK cells with activating profile and increased IL-22 under IFN-beta therapy suggest that IFN-beta treatment might direct NK cells toward a pro-inflammatory status.