Natural killer (NK) cells possess innate immune responses and play a crucial role in regulating autoimmune T cells. NKp46 is a natural cytotoxicity activating receptor exclusively expressed on NK cells. NKp46 plays a pivotal role in NK cell functions because it mediates the lysis of many human tumor cells lines, as well as infected cells. We investigated the expression of NKp46, CD62L and CD44 on NK cells from Multiple Sclerosis (MS) patients and healthy donors (HD). Apheresis blood samples were obtained from MS patients and HD, PBMCs were separated by density gradient centrifugation with lymphocytes separation medium. NK cells were negatively selected using MACS NK isolation kit, and cultured with or without 1 μg/ml influenza vaccine (Flu HA) for 4 hours. Using 6 color flow cytometry, we examined the CD56+ CD3− cells for the expression of NKp46, CD62L and CD44. We observed that MS patients’ NK cells express unusually low frequency of CD56dim CD44+ NKp46+ cells compared to HD. The levels of CD56bright cells expressing CD44+ CD62L+ NKp46+ were comparable among MS patients and HD. Four hours after incubation with Flu HA, the two CD56dim and CD56bright populations expressing NKp46+ completely disappeared leaving one population expressing only CD56dim CD44+. Our findings suggest that CD56dim CD44+ NKp46+ might be involved in the protection against development of MS.