SJL (H‐2^s) female mice are more susceptible than males to experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin‐derived peptides. The reasons for this sexual dimorphism are unclear, but may include such factors as sex‐related differences in immune responsiveness, hormonal effects and sex‐linked genetic factors. Recent evidence indicates that leptin modifies T cell immunity promoting T helper (Th) 1 pro‐inflammatory immune responses. Circulating leptin levels show a marked sexual dimorphism, being higher in females than in males. In the present study, we investigated whether leptin treatment altered the course of relapsing‐remitting EAE, induced by the proteolipid protein peptide (PLP_139–151), in SJL susceptible females and EAE‐resistant males. Administration of leptin to female SJL mice before or after disease onset significantly worsened the disease, with a concomitant increase in the PLP_139–151‐specific delayed‐type hypersensitivity (DTH) reactivity and in vitro IFN‐γ secretion. Leptin treatment at priming with antigen or before disease onset rendered male SJL mice susceptible to EAE, with the appearance of PLP_139–151‐specific DTH reactivity and a switch from a Th2 to Th1 pattern of cytokine release. Our findings indicate that leptin administration to susceptible females resulted in a more severe disease, and that reduced leptin levels in male SJL mice may contribute to the gender‐related differences in the induction phase of EAE.