Background/Aim. Serum neurofilament light chain (sNfL) is a sensitive biomarker of neuroaxonal damage and disease activity in multiple sclerosis (MS). The aim of this study was to investigate changes in sNfL levels following initiation of different disease-modifying therapies (DMTs) in treatment-naive patients with relapsing-remitting MS (RRMS), and to explore potential sex-related differences in treatment response. Methods. The longitudinal study analyzed 78 treatment-naive RRMS patients (40 males, 38 females) initiating their first DMT [injectable (n = 37): interferon beta-1a: Rebif^®, interferon beta-1b: Betaferon^®, glatiramer acetate: Copaxone^®, or oral (n = 41): sphingosine 1-phosphate receptor (S1PR) modulators: fingolimod, ozanimod, ponesimod]. Concentrations of sNfL were measured using enzyme-linked immunosorbent assay – ELISA prior to therapy initiation and after 6 months. Disability was assessed at baseline using Expanded Disability Status Scale – EDSS and Multiple Sclerosis Severity Score – MSSS. Repeated measures analysis was used to evaluate longitudinal changes. Results. A significant reduction in sNfL levels was observed after 6 months of DMT therapy in the examined patients (p < 0.001; partial η² = 0.358). A significant interaction between sex and treatment response was found (p = 0.003), with a more pronounced reduction in sNfL levels observed in females. No significant difference in sNfL reduction was found between injectable therapies and S1PR modulators (p = 0.092), although baseline sNfL levels were higher in the S1PR group (p < 0.001). Conclusion. Initiation of DMTs in RRMS patients was associated with a significant decrease in sNfL levels, suggesting reduced neuroaxonal damage following treatment introduction. Higher baseline sNfL levels in females may indicate potential sex-related differences in neuroaxonal injury. Monitoring sNfL may represent a useful non-invasive biomarker of biological treatment response in RRMS patients.