Objective To compare the diagnostic efficacy of computer-aided diagnosis (CAD) system based on different guidelinesSfor the diagnosis of benign and malignant thyroid nodules. Methods This multicentric prospective study analyzed 453 patients with 521 thyroid nodules visiting the four hospitals of federation between January 2019 and September 2019. All the nodules were confirmed by pathology of surgery or ultrasound guided fine needle aspiration . Using pathology as the gold standard, establish the receiver operating characteristic curve (ROC curve), and obtain the area under the curve (AUC), cut-off value and its corresponding sensitivity, specificity, positive predictive value (PPV), negative Predicted value (NPV). The Z-test was used to compare the AUC between groups. The McNemar test was used to compare the sensitivity and specificity between groups. Result The AUC and sensitivity of the KSThR consensus is higher than the other seven guidelines (P<0.01), the specificity of the BTA guidelines was higher than the other seven guidelines (P<0.01). Conclusion The KSThR consensus has the highest AUC, sensitivity, and the BTA guidelines have the highest specificity.