Background: Prognostic biomarkers are badly needed to direct MS treatment intensity early in the condition Levels of serum neurofilament light chains (sNfL) result from the destruction of central nervous system axons in MS and correlate with the aggressiveness of the disease. Methods: In this prospective cohort study, we identified patients with serum collected within 5 years of first MS symptom onset with more than 15 years of clinical follow-up. Levels of sNfL were quantified in patients and matched controls using digital immunoassay. Results: Sixty-seven patients had a median follow-up period of 17.4 years (range:15.1-26.1). Median serum NfL levels in baseline samples of MS patients was 10.1 pg/ml, 38.5% higher than median levels in 37 controls (7.26pg/ml, p=0.004). Baseline NfL level was most helpful as a predictive marker to rule out progression; patients with levels less 7.62pg/ml were 4.3 times less likely to develop an EDSS score of 34 (p=0.001) and 7.1 times less likely to develop progressive MS (p=0.054). Patients with the highest NfL levels (3rd-tertile, >13.2 pg/ml) progressed most rapidly with an EDSS annual rate of 0.16 (p=0.004), remaining significant after adjustment for sex, age, and disease-modifying treatment (p=0.022). Conclusions: This study demonstrates that baseline sNfL is associated with long term disease progression.