BACKGROUND Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS) with unknown etiology and variable clinical evolution. Although the role of serum progranulin levels in the pathogenesis of MS remains unclear, it is well known that progranulin is involved in several physiological and pathophysiological process of CNS including modulation of neurite outgrowth, neuronal differentiation, and neuronal survival. Therefore, in this study, we aimed to measure serum levels of progranulin in patients with neuromyelitis optica (NMO) and relapsing-remitting multiple sclerosis (RRMS) in comparison with healthy control subjects. METHODS In a case-control study, plasma was collected from healthy controls (n = 37) and also patients with RRMS (n = 115) and NMO (n = 33). Serum level measurement of progranulin was performed using a sandwich ELISA method. RESULTS The serum levels of progranulin were 65.07 ± 11.64, 56.81 ± 10.34, and 47.73 ± 10.37 in NMO and MS patients and healthy controls, respectively, showing a statistically significant difference between them (P = 0.00). Furthermore, we found a positive correlation between serum levels of progranulin and EDSS of patients (r = 0.79 and P = 0.00). CONCLUSIONS The present study demonstrated that progranulin is up-regulated in MS patients and our findings strengthen the evidence for progranulin being involved in the pathogenesis of MS. However, further studies will be required to establish progranulin as an important marker for MS.