Recent findings indicate a pathogenic involvement of IL‐17‐producing CD8+ T cells in multiple sclerosis (MS). IL‐17 production has been attributed to a subset of CD8+ T cells that belong to the mucosal‐associated invariant T (MAIT) cell population. Here, we report a reduction of CD8+ MAIT cells in the blood of MS patients compared with healthy individuals, which significantly correlated with IL‐18 serum levels in MS patients. In vitro stimulation of peripheral blood mononuclear cells from healthy individuals and MS patients with IL‐18 specifically activated CD8+ MAIT cells. Moreover, IL‐18 together with T‐cell receptor stimulation induced, specifically on CD8+ MAIT cells, an upregulation of the integrin very late antigen‐4 that is essential for the infiltration of CD8+ T cells into the CNS. Notably, we were able to identify CD8+ MAIT cells in MS brain lesions by immunohistochemistry while they were almost absent in the cerebrospinal fluid (CSF). In summary, our findings indicate that an IL‐18–driven activation of CD8+ MAIT cells contributes to their CNS infiltration in MS, in turn leading to reduced CD8+ MAIT‐cell frequencies in the blood. Therefore, CD8+ MAIT cells seem to play a role in the innate arm of immunopathology in MS.