This study aims to compare NK cells obtained from multiple sclerosis (MS) patients receiving interferon-beta 1 and fingolimod therapies. Fingolimod reduced the CD56(bright) NK cell subset. The remaining CD56(dim) NK cells displayed NKG2D, NKp46, CD107a, and IFN-gamma levels similar to those from the patients under interferon-beta 1 therapy. Alternatively, comparative transcriptomics and pathway analyses revealed significant distinctions between two therapy modalities. Molecular signature of the CD56(dim) NK cells from fingolimod-treated MS patients was closely associated to those from healthy subjects. The basic assets of NK cells were modestly influenced by interferon-beta 1 and fingolimod, however transcriptomics showed profound alterations in NK responses.