BACKGROUND: Biomarkers are needed to track progression in MS trials. Neurofilament heavy chain (NfH) has been underutilized due to assay limitations. OBJECTIVE: To investigate the added value of cerebrospinal fluid (CSF) NfH in secondary progressive multiple sclerosis (SPMS) using contemporary immunoassays. METHODS: This exploratory study was part of the MS-SMART trial. Clinical assessments (including expanded disability status scale, upper and lower limb function, visual acuity and symbol digit modalities test (SDMT)), CSF and serum sampling were acquired at baseline ( RESULTS: Baseline CSF NfH and NfL correlated with information processing speed at 96 weeks, with CSF NfH showing stronger correlations ( CONCLUSION: CSF neurofilaments are better outcomes than serum neurofilaments in small SPMS studies. CSF NfH and NfL variably predict worsening hand function, information processing speed and brain volume loss, possibly reflecting complementary aspects of neurodegeneration.