Carpal tunnel syndrome (CTS) accompanied by secondary axonal degeneration cannot be clearly dis-criminated using the current cross-validated ultrasound severity classification system. This study aimed at exploring cut-off values of ultrasound parameters, including wrist cross-sectional area (W-CSA), wrist perimeter (W-P), ratio of cross-sectional area (R-CSA) and perimeter (R-P), changes of CSA and P from wrist to one third distal forearm (ΔCSA&ΔP) for differentiation. Seventy-three patients (13 male and 60 female) were assigned into group A (demyelination only, n = 40) and group B (demyelination with sec-ondary axonal degeneration, n = 33) based on the outcomes of nerve conduction studies (NCS). Receiver Operative Characteristics (ROC) curves were plotted to obtain sensitivity, specificity, and accuracy of cut-off values for all the ultrasound parameters. The overall identified cut-off values (W-CSA 12.0 mm2, W-P 16.27 mm, R-CSA 1.85, R-P 1.48, ΔCSA 6.98 mm2, ΔP 5.77 mm) had good sensitivity (77.1–88.6%), fair specificity (40–62.2%) and fair-to-good accuracy (0.676–0.758). There were also significant differences in demographics (age and severity gradation, P＜0.001), NCS findings (wrist motor latency and conduction velocity, P＜0.0001; wrist motor amplitude, P＜0.05; distal sensory latency, P＜0.05; sensory amplitude, P＜0.001) and ultrasound measurements (W-CSA, W-P, R-CSA, R-P, ΔCSA&ΔP, P＜0.05) between groups. These findings suggest that ultrasound can be potentially used to differentiate demyelinating CTS with sec-ondary axonal degeneration and provide better treatment guidance.