Computer-aided diagnosis (CAD) and other risk stratification systems may improve ultrasound image interpretation. This prospective study aimed to compare the diagnostic performance of CAD and the European Thyroid Imaging Reporting and Data System (EU-TIRADS) classification applied by physicians with S-Detect 2 software CAD based on Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and combinations of both methods (MODELs 1 to 5). In all, 133 nodules from 88 patients referred to thyroidectomy with available histopathology or with unambiguous results of cytology were included. The S-Detect system, EU-TIRADS, and mixed MODELs 1–5 for the diagnosis of thyroid cancer showed a sensitivity of 89.4%, 90.9%, 84.9%, 95.5%, 93.9%, 78.9% and 93.9%; a specificity of 80.6%, 61.2%, 88.1%, 53.7%, 73.1%, 89.6% and 80.6%; a positive predictive value of 81.9%, 69.8%, 87.5%, 67%, 77.5%, 88.1% and 82.7%; a negative predictive value of 88.5%, 87.2%, 85.5%, 92.3%, 92.5%, 81.1% and 93.1%; and an accuracy of 85%, 75.9%, 86.5%, 74.4%, 83.5%, 84.2%, and 87.2%, respectively. Comparison showed superiority of the similar MODELs 1 and 5 over other mixed models as well as EU-TIRADS and S-Detect used alone (p-value < 0.05). S-Detect software is characterized with high sensitivity and good specificity, whereas EU-TIRADS has high sensitivity, but rather low specificity. The best diagnostic performance in malignant thyroid nodule (TN) risk stratification was obtained for the combined model of S-Detect (“possibly malignant” nodule) and simultaneously obtaining 4 or 5 points (MODEL 1) or exactly 5 points (MODEL 5) on the EU-TIRADS scale.