BACKGROUND Our objective in this study was to assess the diagnostic utility of the median nerve cross-sectional area (CSA) at the wrist, the wrist-forearm ratio, and the wrist-forearm difference in patients with and without carpal tunnel syndrome (CTS). METHODS Individuals with electrodiagnostically proven CTS and asymptomatic control subjects were recruited prospectively from among patients referred to our electrodiagnostic laboratory. Blinded measurements of CSA were made from transverse sonographic images of the median nerve at the wrist (pisiform) and mid-forearm. RESULTS Fifty-five cases and 49 controls were recruited. Wrist median nerve CSA (15 vs. 9 mm²; P < 0.0001), wrist-forearm ratio (3.09 vs. 1.90 mm²; P < 0.0001), and wrist-forearm difference (10 vs. 4 mm²; P < 0.0001) were all significantly larger in CTS cases (areas under the curve = 0.89, 0.82, and 0.88, respectively). CONCLUSIONS Median nerve CSA at the carpal tunnel inlet and wrist-forearm difference provides the best discrimination between patients with CTS and controls according to receiver operator characteristic (ROC) analysis. Age, gender, height, weight, and wrist size have no effect on CSA.