OBJECTIVE. The purpose of this study was to explore whether a quantitative framework can be used to sonographically differentiate benign and malignant thyroid nodules at a level comparable to that of experts. MATERIALS AND METHODS. A dataset of ultrasound images of 92 biopsy-confirmed nodules was collected retrospectively. The nodules were delineated and annotated by two expert radiologists using the standardized Thyroid Imaging Reporting and Data System lexicon of the American College of Radiology. In the framework studied, quantitative features of echogenicity, texture, edge sharpness, and margin curvature properties of thyroid nodules were analyzed in a regularized logistic regression model to predict malignancy of a nodule. The framework was validated by leave-one-out cross-validation technique, and ROC AUC, sensitivity, and specificity were used to compare with those obtained with six expert annotation-based classifiers. RESULTS. The AUC of the proposed method was 0.828 (95% CI, 0.715-0.942), which was greater than or comparable to that of the expert classifiers, for which the AUC values ranged from 0.299 to 0.829 (p = 0.99). Use of the proposed framework could have avoided biopsy of 20 of 46 benign nodules in a curative strategy (at sensitivity of 1, statistically significantly higher than three expert classifiers) or helped identify 10 of 46 malignancies in a conservative strategy (at specificity of 1, statistically significantly higher than five expert classifiers). CONCLUSION. When the proposed quantitative framework was used, thyroid nodule malignancy was predicted at the level of expert classifiers. Such a framework may ultimately prove useful as the basis for a fully automated system of thyroid nodule triage.