Background Thyroid cancer diagnosis has evolved to include computer-aided diagnosis (CAD) approaches to overcome the limitations of human ultrasound feature assessment. This study aimed to evaluate the diagnostic performance of a CAD system in thyroid nodule differentiation using varied settings. Methods Ultrasound images of 205 thyroid nodules from 198 patients were analysed in this retrospective study. AmCAD-UT software was used at default settings and 3 adjusted settings to diagnose the nodules. Six risk-stratification systems in the software were used to classify the thyroid nodules: The American Thyroid Association (ATA), American College of Radiology Thyroid Imaging, Reporting, and Data System (ACR-TIRADS), British Thyroid Association (BTA), European Union (EU-TIRADS), Kwak (2011) and the Korean Society of Thyroid Radiology (KSThR). The diagnostic performance of CAD was determined relative to the histopathology and/or cytology diagnosis of each nodule. Results At the default setting, EU-TIRADS yielded the highest sensitivity, 82.6% and lowest specificity, 42.1% while the ATA-TIRADS yielded the highest specificity, 66.4%. Kwak had the highest AUROC (0.74) which was comparable to that of ACR, ATA, and KSThR TIRADS (0.72, 0.73, and 0.70 respectively). At a hyperechoic foci setting of 3.5 with other settings at median values; ATA had the best-balanced sensitivity, specificity and good AUROC (70.4%; 67.3% and 0.71 respectively). Conclusion The default setting achieved the best diagnostic performance with all TIRADS and was best for maximizing the sensitivity of EU-TIRADS. Adjusting the settings by only reducing the sensitivity to echogenic foci may be most helpful for improving specificity with minimal change in sensitivity.