We analyzed the serum and cerebrospinal fluid (CSF) leptin secretion and the interaction between serum leptin and CD4⁺CD25⁺ regulatory T cells (T_Regs) in naïve-to-therapy relapsing-remitting multiple sclerosis (RRMS) patients. Leptin production was significantly increased in both serum and CSF of RRMS patients and correlated with IFN-γ secretion in the CSF. T cell lines against human myelin basic protein (hMBP) produced immunoreactive leptin and up-regulated the expression of the leptin receptor (ObR) after activation with hMBP. Treatment with either anti-leptin or anti-leptin-receptor neutralizing antibodies inhibited in vitro proliferation in response to hMBP. Interestingly, in the RRMS patients, an inverse correlation between serum leptin and percentage of circulating T_Regs was also observed. To better analyze the finding, we enumerated T_Regs in leptin-deficient (ob/ob) and leptin-receptor-deficient (db/db) mice and observed the significant increase in T_Regs. Moreover, treatment of WT mice with soluble ObR fusion protein (ObR:Fc) increased the percentage of T_Regs and ameliorated the clinical course and progression of disease in proteolipid protein peptide (PLP_139–151)-induced relapsing-experimental autoimmune encephalomyelitis (R-EAE), an animal model of RRMS. These findings show an inverse relationship between leptin secretion and the frequency of T_Regs in RRMS and may have implications for the pathogenesis of and therapy for multiple sclerosis.