BACKGROUND: Differential diagnosis of benign and malignant thyroid imaging reporting and data system category 4 (TI-RADS-4) nodules can be difficult using conventional ultrasound (US). This study aimed to evaluate whether multimodal ultrasound imaging can improve differentiation and characterization of benign and malignant TI-RADS-4 nodules. METHODS: Multimodal ultrasound imaging, including US, superb microvascular imaging (SMI), and real-time elastography (RTE), were performed on 196 TI-RADS-4 nodules (78, benign; 118, malignant) in 170 consecutive patients. The sensitivity, specificity, accuracy, false negative rate (FNR), and false positive rate (FPR) of each single method and that of multimodal US imaging were determined by comparison with surgical pathology results. RESULTS: The sensitivity, specificity, accuracy, FNR, and FPR for US were 65.25%, 69.23%, 66.84%, 34.75%, 30.77%, respectively; for SMI were 77.97%, 93.59%, 84.18%, 22.03%, 6.41%, respectively; RTE, 80.51%, 84.62%, 82.14%, 19.49%, 15.38%; and for multimodal US imaging were 94.08%, 87.18%, 91.33%, 6.93%, 12.82%, respectively. The areas under the received operating characteristic curve for US, SMI, RTE, and multimodal US imaging in evaluating benign and malignant TI-RADS-4 nodules were 67.2%, 84.40%, 86.60%, and 95.50%, respectively. CONCLUSIONS: The initial clinical results suggest that multimodal US imaging improves the diagnostic accuracy of TI-RADS-4 nodules and provides additional information for differentiating malignant and benign nodules.