OBJECTIVES: The purpose of this study was to evaluate the role of the radiomics score using US images to predict malignancy in AUS/FLUS and FN/SFN nodules. METHODS: One hundred fifty-five indeterminate thyroid nodules in 154 patients who received initial US-guided FNA for diagnostic purposes were included in this retrospective study. A representative US image of each tumor was acquired, and square ROIs covering the whole nodule were drawn using the Paint program of Windows 7. Texture features were extracted by in-house texture analysis algorithms implemented in MATLAB 2019b. The LASSO logistic regression model was used to choose the most useful predictive features, and ten-fold cross-validation was performed. Two prediction models were constructed using multivariable logistic regression analysis: one based on clinical variables, and the other based on clinical variables with the radiomics score. Predictability of the two models was assessed with the AUC of the ROC curves. RESULTS: Clinical characteristics did not significantly differ between malignant and benign nodules, except for mean nodule size. Among 730 candidate texture features generated from a single US image, 15 features were selected. Radiomics signatures were constructed with a radiomics score, using selected features. In multivariable logistic regression analysis, higher radiomics score was associated with malignancy (OR = 10.923; p < 0.001). The AUC of the malignancy prediction model composed of clinical variables with the radiomics score was significantly higher than the model composed of clinical variables alone (0.839 vs 0.583). CONCLUSIONS: Quantitative US radiomics features can help predict malignancy in thyroid nodules with indeterminate cytology.