Specific T-cell subsets and their ability to produce cytokines have been involved in concepts of multiple sclerosis (MS) pathogenesis. Evidence to link cytokine producing T-cell subsets to magnetic resonance imaging (MRI) features of tissue destruction, however, is limited. Cytokine flow cytometry was performed in 124 patients with different subtypes of MS. In a subgroup of 69 patients, from whom longitudinal MRI was available, the ability of circulating types 1 and 2 helper T cells to produce cytokines was correlated to changes in T1 hypointense and T2 hyperintense lesion load (LL) on brain MRI during 3 years of follow-up. Significant negative correlations were found between baseline CD8(+) T-cell subsets producing IL-2, IL-4 or IL-13 and the change in T1 LL. Subgroup analyses demonstrated that in RRMS, CD8(+) T cells producing IL-2, IL-4 or IL-13, and in PPMS, CD8(+) IL-10(+) T cells correlated negatively with T1 LL. To our knowledge, this study provides the first direct immunophenotypic evidence of cytokine producing CD8(+) T cells being directly related to long-term development of MRI features of demyelination and axonal loss.