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Background Neurofilament light chains (sNfl) are proteins of the nervous system that leach into blood during periods of damage. In MS, elevated sNfl predicts relapses and disease progression in trials but ‘real world’ data is less clear.Methods Patients ( n=222) from an Australian MS clinic donated serum samples (2021/2022). Patients with primary and secondary progressive MS were excluded. Clinical (EDSS, relapse rate) and radiological activity were recorded 6 months before and for 3 subsequent years to determine rates of NEDA (no evidence of disease activity). Patients with disease activity before the sample (PRE-Nfl) were analysed independently of those with subsequent activity (POST-Nfl). sNfl was measured using the SIMOA platform (Quanterix) with appropriate controls. Mean sNfl levels were compared between groups using ANOVA.Results Patients were 44.9 years old and 73.4% were female. 95% of patients were treated, 84% with high efficacy therapy (HET). 87% exhibited NEDA(193/222) over a median of 31 months. NEDA patients had a mean sNfl of 8.8g/ml (95% CI 8.1 to 9.7) compared to active patients, 18.2pg/ml (95%CI 11.1 to 25.3; p < 0.001 Mann Whitney U test). Both PRE-Nfl (23.6 pg/ml) and POST-Nfl patients (14.4 pg/ml) sNfl were increased compared to NEDA patients (p < 0.001, Boot-strapped ANOVA). In POST-NFL patients, EDSS progression was most frequent (55%,11/20).Conclusion Serum Nfl is a useful biomarker to identify future disease activity in MS clinic patients. In patients with a level of 14 pg/ml or greater, disease activity occurred within 3 years, usually disability progression, despite HET.