Objective: Multiple sclerosis (MS) is a chronic neuroinflammatory disease, characterizes by demyelination in the central nervous system (CNS). Co-stimulatory molecules such as CD137 (4-1 BB) play a major role in the activation of lymphocytes in CNS. The exact immunopathogenesis of MS is unknown. Hence, detection of specific biomarkers in the process of MS disease can lead to new therapeutic approaches. This study aimed to compare plasma sCD137 levels in relapsing-remitting multiple sclerosis (RRMS) patients with healthy controls in Isfahan province. Methods: Plasma sCD137 level was measured by enzyme-linked immune sorbent assays (ELISA) in 36 RRMS patients as well as 52 (age and sex-matched) healthy controls and the results were compared. Results: The plasma sCD137 level in studied RRMS patients was significantly higher in the patient group compared to the healthy controls (P- value=0.027). In addition, there was no significant association between age, sex, job and education level, with plasma sCD137 level in both the control and the case groups (P value>0.05). There was no correlation between mean of sCD137 and EDSS score, age of onset, duration of disease as well as serum 25 (OH) D concentrations of the patients. Conclusion: High plasma sCD137 level was detected in RRMS patients when compared with the controls, which may indicate the possible role of this biomarker in the immunopathogenesis of MS. Since CD137 can affect T lymphocytes activation and apoptosis, further studies are needed to elucidate its exact role in the pathogenesis of MS.