Objectives: To assess the prognostic role of serum neurofilament light chains (Nfls) for Clinically Defined Multiple Sclerosis (CDMS) and McDonald 2017 MS in patients with Clinically Isolated Syndromes (CIS). Methods: we retrospectively analyzed data of patients admitted at our neurological department between 2000 to 2015 for a first demyelinating event. We evaluated baseline serum Nfls in addition to CSF, MRI, and clinical data. Results: Amongst 222 patients who were enrolled (mean follow-up 100.6 months), 45 patients (20%) developed CDMS and 141 patients (63.5%) developed 2017 MS at two years. Serum Nfls (median 22.0, IQR 11.6-40.4 pg/ml) were noticeably increased in patients who have suffered a recent relapse, with a high number of T2 and Gd enhancing lesions at baseline MRI. Serum Nfls were prognostic for both CDMS and McDonald 2017 MS, with a three-fold and a two-fold respective reduction in CDMS and 2017 MS risk in those patients with low and extremely low levels of Nfl. The results remained unchanged subsequent to adjustment for such established MS prognostic factors as oligoclonal bands’ presence, Gd-enhancing lesion, and a high T2 lesion load at baseline MRI. Nfls were associated with baseline disability but not at follow-up. Conclusions: Serum Nfls have a prognostic value for CIS patient conversion to MS. Nfls might play a twin role as biomarkers in MS as peak level measurements can act as a quantitative marker of serious inflammatory activity, while steady-state levels can be a reflection of neurodegenerative and chronic inflammatory processes.