Abstract Background MS is characterized by persistent central nervous system (CNS) inflammation. Investigating the CNS-compartmentalized inflammation associated with progressive MS could uncover new biomarkers and therapeutic targets. Cerebrospinal fluid (CSF) interleukin-6 (IL-6) can be markedly elevated in neuroinflammatory conditions, such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease. This study investigated the association between CSF IL-6 levels, progressive disease, and disease severity in MS. Methods Advanced technologies, including single-molecule arrays and microfluidics, were used to analyse CSF samples from individuals with MS at the time of diagnosis for IL-6. IL-6 levels were then correlated with clinical course, disease severity, and other known biomarkers associated with inflammation and disease severity. Results Elevated IL-6 levels in the CSF were found in individuals with progressive MS, and CSF IL-6 showed positive correlations with the Expanded Disability Status Scale, the Multiple Sclerosis Severity Score, and CSF glial fibrillary acidic protein levels. Conclusions IL-6 in CSF indicates ongoing CNS inflammation and may contribute to the compartmentalized inflammation associated with disease progression and overall disease severity.