Objectives-Ultrasonography (US) of the median nerve has been increasingly studied and used for confirmation of carpal tunnel syndrome (CTS). However, a consensus on the choice of parameters to be evaluated is still not established. The aim of this diagnostic accuracy study was to assess the diagnostic value of multiple parameters individually, as well as in different combinations of variable complexity, and to find an optimal approach for US-based confirmation of a CTS diagnosis. Methods-All participants completed clinical and electrophysiologic evaluations, and their hands were scanned with a 5-13-MHz linear US transducer. Eighty-six patients with CTS (135 symptomatic hands) and 50 control participants (93 asymptomatic hands) were analyzed. The median nerve was recorded transversely at the forearm, at the carpal tunnel inlet, in the mid tunnel, and at the carpal tunnel outlet. For determining the parameters' diagnostic value, sensitivities, specificities, and area under the curve (AUC) values were calculated. Results-The inlet cross-sectional area, inlet circumference, and outlet cross-sectional area of the median nerve had the highest AUCs (0.962, 0.920, and 0.913, respectively), sensitivities (87.4%, 80.0%, and 74.1%), and specificities (94.6%, 91.4%, and 92.5%) among single-measurement parameters. An analysis of 2-level parameters (wrist-to-forearm-ratio, inlet-to-outlet-ratio, outlet-to-forearm-ratio, and inlet-outlet mean) yielded the highest AUC (0.974) for the mean cross-sectional area of the median nerve [(inlet+outlet cross-sectional area)/2], with high sensitivity (93.5%) and specificity (91.1%). A compound regression-based index yielded a marginally higher AUC (0.989) than the previously mentioned parameters. Conclusions-Results of the study show that the mean cross-sectional area and inlet cross-sectional area may be valid and easy-to-acquire parameters for routine clinical use in confirming CTS.