CSF and serum NfL correlated significantly in the total group (ρ 0.532, <i>p</i> < 0.001) and even more significantly in the subgroup of patients with future CDMS diagnosis (ρ 0.773, <i>p</i> < 0.001). sNfL was higher in patients than in controls (geometric mean 6.1 pg/mL, <i>p</i> < 0.001), and was highest in ADS presenting with encephalopathy (acute disseminated encephalomyelitis, n = 28, 100.4 pg/mL), followed by patients without encephalopathy (ADS-) with future CDMS diagnosis (n = 40, 32.5 pg/mL), and ADS- who remained monophasic (n = 34, 17.6 pg/mL). sNfL levels higher than a median of 26.7 pg/mL at baseline are associated with a shorter time to CDMS diagnosis in ADS- (<i>p</i> = 0.045).