There is increasing interest in the development of multiple sclerosis (MS) biomarkers that reflect central nervous system tissue injury to determine prognosis. We aimed to assess the prognostic value of kinesin superfamily motor protein KIF5A in MS by measuring levels of KIF5A in cerebrospinal fluid (CSF) combined with analysis of single nucleotide polymorphisms (SNPs; rs12368653 and rs703842) located within a MS susceptibility gene locus at chromosome 12q13-14 region. Enzyme-linked immunosorbent assay was used to measure KIF5A in CSF obtained from two independent biobanks comprising non-inflammatory neurological disease controls (NINDC), clinically isolated syndrome (CIS) and MS cases. CSF KIF5A expression was significantly elevated in progressive MS cases compared with NINDCs, CIS and relapsing-remitting MS (RRMS). In addition, levels of KIF5A positively correlated with change in MS disease severity scores (EDSS, MSSS and ARMSSS), in RRMS patients who had documented disease progression at 2-year clinical follow-up. Copies of adenine risk alleles (AG/AA; rs12368653 and rs703842) corresponded with a higher proportion of individuals in relapse at the time of lumbar puncture (LP), higher use of disease-modifying therapies post LP and shorter MS duration. Our study suggests that CSF KIF5A has potential as a predictive biomarker in MS and further studies into the potential prognostic value of analysing MS susceptibility SNPs should be considered.