Objective To investigate the value of computer-aided diagnosis (CAD) system in assessing thyroid nodules concurrent with Hashimoto's thyroiditis (HT). Methods Totally 148 patients with 193 thyroid nodules were enrolled. A radiologist assessed the nodules using a thyroid ultrasound CAD system. Additionally, the nodules were evaluated by one experienced radiologist alone, and one training radiologist without and with CAD assistance. The diagnostic performance was compared between the CAD system and the experienced radiologist, and the training radiologist without and with CAD assistance. Results The CAD system demonstrated a similar sensitivity to that of the experienced radiologist in diagnosing thyroid cancers (89.8% versus 92.4%, P > .05). The specificity and accuracy of the CAD system were lower than that of the experienced radiologist in assessing the nodules with diffusedly altered glands (specificity, 60.0% versus 81.7%, P = .007; accuracy, 77.5% versus 88.1%, P = .011). With CAD assistance, the training radiologist had improved sensitivity and accuracy that increased to 87.9% and 86.8% in classifying nodules with sonographically evident HT (both P = .012). Conclusion The CAD system has comparable sensitivity, but lower specificity compared with the experienced radiologist in diagnosing thyroid malignancies concurrent with HT. For a radiologist with less experience, the CAD system can help improve the diagnostic performance by increasing sensitivity and accuracy in assessing thyroid nodules with diffusely altered parenchyma.