Multiple sclerosis (MS) is a chronic autoimmune disease where activated immune cells can attack oligodendrocytes causing damage to the myelin sheath. Several molecular mechanisms are responsible for the auto-activation of immune cells such as RNA interference (RNAi) through microRNAs (miRNAs or miRs). In the present study, the role of miR-155 in regulating CD8 + T-cell activity in patients with relapsing-remitting multiple sclerosis (RRMS) was investigated, in terms of its migratory functions with regard to intracellular adhesion molecule-1 (ICAM1) and integrin subunit β2 (ITGB2), and its cytotoxic proteins, perforin and granzyme B. Gene expression of miR-155, ICAM1, ITGB2, perforin and granzyme B was evaluated following epigenetic modulations using reverse transcription-quantitative polymerase chain reaction in CD8 + T-cells isolated from blood samples of patients with RRMS and compared to healthy controls. The ectopic expression of miR-155 resulted in a persistent downregulation in all genes of interest related to CD8 + T-cell activation that were positively correlated with the Expanded Disability Status Scale of patients. The present study revealed the interplay between miR-155, ICAM1, and ITGB2, shedding light on their beneficial use as possible therapeutic regulators and diagnostic biomarkers of disease. Moreover, epigenetic modulations enhancing the efficacy of disease-modifying therapies (DMTs) may be employed as personalized therapy, to decrease the side effects of DMTs and improve the outcomes of patients.