Sex differences in the incidence and severity of multiple sclerosis (MS) have long been recognized, but the underlying mechanisms remain poorly defined. Here, we elucidate the cellular and molecular underpinnings of why male sex is associated with a more aggressive and debilitating disease course. Using an adoptive transfer model of EAE to examine disease driven by CD4+ T helper 17 (Th17 cells), we find that male Th17 cells induced disease of increased severity relative to female Th17 cells, irrespective of whether the cells were transferred to male or female recipients. Both female and male peripheral Th17 exhibited phenotypic plasticity as early as disease onset, producing either IL-17 and IFN together or IFN alone; however, a higher proportion of male Th17 produced IFN throughout the disease course, with increased expression of both IFN and GM-CSF from CNS-infiltrating Th17 cells correlating with severe disease in males. Further, male cells upregulated signature genes previously associated with phenotypically plastic Th17 responses. Intriguingly, male sex chromosomal complement, rather than androgens, was responsible for increased pathogenicity, and an X-linked immune regulator, Jarid1c, was downregulated in pathogenic male Th17. Additionally, Jarid1c expression is reduced in CD4+ T cells derived from men with MS. Together, our data indicate that male sex is a critical regulator of Th17 cell plasticity and CNS autoimmunity.