To summarize the current evidence on the clinical significance of interleukin (IL)-6 in multiple sclerosis (MS).

IL-6 is a promising biomarker under investigation across inflammatory diseases; however, its diagnostic relevance in MS and ability to discriminate between demyelinating diseases remain uncertain.

We searched five databases (PubMed, Embase, Scopus, Web of Science and Google Scholar) up to October 2025 for observational studies on IL-6 and MS. We included only studies that quantified IL-6 in both CSF and serum. Random-effects meta-analyses were conducted when possible. Risk of bias was assessed using the Newcastle–Ottawa scale.

15 studies (773 patients) were included. Plasma IL-6 levels (pg/mL) were not significantly different in MS versus controls (SMD −0.06; 95% CI −0.36 to 0.25; I²=63%), and the same held in CSF (SMD 0.33; 95% CI −0.37 to 1.02; I²=92%). In subtype comparisons, RRMS did not differ from PPMS in plasma (SMD −0.85; 95% CI −0.85 to 0.03; I²=0%) or CSF (SMD 0.45; 95% CI −0.77 to 1.67; I²=85.62%). RRMS and SPMS likewise showed no plasma difference (SMD −0.34; 95% CI −1.14 to 0.45; I²=69.57%), whereas in CSF IL-6 levels were significantly higher in RRMS than in SPMS (SMD 0.75; 95% CI −0.31 to 1.19; I²=0%). Finally, OCB+ and OCB− MS did not differ in plasma (SMD −0.10; 95% CI −1.05 to −0.85; I²=0%) or CSF (SMD −0.49; 95% CI −1.07 to −0.09; I²=62.49%). All studies showed low to moderate risk of bias.

IL-6 shows no consistent serum or CSF differences between MS and controls, nor across subtypes or OCB status. Current evidence does not support IL-6 as a stand alone diagnostic marker; further higher quality studies are needed.