Background and Purpose Selective agonists of the sigma‐1 receptor (σ1 protein) are generally reported to protect against neuronal damage and modulate oligodendrocyte differentiation. Human and rodent lymphocytes possess saturable, high‐affinity binding sites for compounds binding to the σ1 protein and potential immunomodulatory properties have been described for σ1 protein ligands. Experimental autoimmune encephalomyelitis (EAE) is recognized as a valuable model of the inflammatory aspects of multiple sclerosis (MS). Here, we have assessed the role of a σ1 protein agonist, containing the tetrahydroisoquinoline‐hydantoin structure, in EAE. Experimental Approach EAE was induced in SJL/J female mice by active immunization with myelin proteolipid protein (PLP)139–151 peptide. The σ1 protein agonist was injected i.p. at the time of immunization (day 0). Disease severity was assessed clinically and by histopathological evaluation of the CNS. Phenotyping of B‐cell subsets and regulatory T‐cells were performed by flow cytometry in spleen and cervical lymph nodes. Key Results Prophylactic treatment of EAE mice with the σ1 protein agonist prevented mononuclear cell accumulation and demyelination in brain and spinal cord and increased T2 B‐cells and regulatory T‐cells, resulting in an overall reduction in the clinical progression of EAE. Conclusions and Implications This σ1 protein agonist, containing the tetrahydroisoquinoline‐hydantoin structure, decreased the magnitude of inflammation in EAE. This effect was associated with increased proportions of B‐cell subsets and regulatory T‐cells with potential immunoregulatory functions. Targeting of the σ1 protein might thus provide new therapeutic opportunities in MS.