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Multiple sclerosis (MS) is an autoimmune, neurological disease. We investigated genome-wide DNA methylation profiles of CD4+ and CD8+ T cells from MS patients and healthy controls at baseline and a follow-up visit. Patients were all treatment-naïve at baseline, and either on treatment or remained untreated at the follow-up visit. MS patients show more changes in their T cell DNA methylation profiles as compared to healthy controls over time, with the most pronounced differences observed in the untreated MS patients. These findings underline the potential of DNA methylation as biomarkers in MS. [Display omitted] • Genome-wide DNA methylation profiles were obtained from MS patients and healthy controls at baseline and one follow-up visit. • MS patients were treatment-naïve at baseline, and untreated or on treatment with immunomodulatory drugs at follow-up. • MS patients show more changes in their DNA methylation profiles compared to healthy controls over time. • Untreated MS patients show more differential DNA methylation at follow-up as compared to treated MS patients. • There is an abundance of hypermethylated DMPs in CD8+ T cells from treated and untreated MS patients at the follow-up visit. [ABSTRACT FROM AUTHOR]