Huntington's disease-like 2 (HDL2) closely resembles Huntington's disease (HD) in clinical and pathological features. Neurofilament light chain (NfL) is an important biomarker in HD research and holds potential in HDL2. To evaluate NfL's utility in HDL2, a comparative analysis among HDL2 (n = 12), HD (n = 9), and unaffected controls (n = 9) was conducted. Employing a cross-sectional design, NfL levels were assessed in blood plasma. Concentrations were notably elevated in both HD and HDL2 groups compared to controls. HD patients displayed higher NfL levels than HDL2, possibly reflecting disease duration differences. NfL effectively distinguished HDL2 from controls, highlighting its promise as a possible biomarker in HDL2 research.