To evaluate the diagnostic efficacy and clinical value of contrast-enhanced ultrasonography (CEUS) plus TI-RADS classification in benign and malignant thyroid tumors compared with either method alone.The informed consent was signed all patients. A total of 370 patients with thyroid tumors of TI-RADS category 3 and 4 were recruited, with 432 thyroid nodules. They respectively received routine ultrasonography and CEUS. The nodules were reclassified according to CEUS scoring, and a combined diagnosis was made. The pathological results were taken as the gold standard. The sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and area under the ROC curve were calculated for the 3 diagnostic methods. The diagnostic efficacy was compared by using Student t test, Pearson chi-square (χ) test, McNemar chi-square (χ) test or Z test. Student t test and logistic regression were employed for comparing different imaging features of benign and malignant thyroid tumors on CEUS and risk analysis.Of 432 thyroid nodules, there were 258 malignant nodules (59.72%) and 174 benign ones (40.28%). By logistic regression, 6 suspicious features on CEUS were considered significant for differentiating malignant from benign tumors: slow entry of contrast agents during enhancement stage (OR = 15.610, P = .001), slow time to peak (OR = 7.416, P = .002), non-uniform enhancement (OR = 10.076, P = .023), enhancement pattern (irregular) (OR = 36.233, P = .002), enhancement boundary (unclear) (OR = 25.300, P = .012), and no ring-like enhancement (OR = 25.297, P = .004). CEUS plus TI-RADS classification showed a higher diagnostic efficacy for differentiating between benign and malignant thyroid tumors. The Se was 85.66% (0.806-0.896), Sp 83.33% (0.768-0.884), PPV 88.40% (0.836-0.919), NPV 79.67% (0.729-0.851), and AUC 0.867 ± 0.019 (0.815-0.889). The above indicators were of statistical significance as compared with TI-RADS classification or CEUS alone (P <.05).CEUS can more clearly visualize microvascular distribution of the nodules and offers a new approach to diagnose benign and malignant thyroid tumors. TI-RADS classification plus CEUS is more accurate than TI-RADS classification alone. This combined approach is worthy of clinical popularization.