Background The incidence and mortality of thyroid cancer, including thyroid nodules > 4 cm, have been increasing in recent years. The current evaluation methods are based mostly on studies of patients with thyroid nodules < 4 cm. The aim of the current study was to establish a risk stratification model to predict risk of malignancy in thyroid nodules > 4 cm. Methods A total of 279 thyroid nodules > 4 cm in 267 patients were retrospectively analyzed. Nodules were randomly assigned to a training dataset (n = 140) and a validation dataset (n = 139). Multivariable logistic regression analysis was applied to establish a nomogram. The risk stratification of thyroid nodules > 4 cm was established according to the nomogram. The diagnostic performance of the model was evaluated and compared with the American College Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS), Kwak TI-RADS and 2015 ATA guidelines using the area under the receiver operating characteristic curve (AUC). Results The analysis included 279 nodules (267 patients, 50.6 +/- 13.2 years): 229 were benign and 50 were malignant. Multivariate regression revealed microcalcification, solid mass, ill-defined border and hypoechogenicity as independent risk factors. Based on the four factors, a risk stratified clinical model was developed for evaluating nodules > 4 cm, which includes three categories: high risk (risk value = 0.8-0.9, with more than 3 factors), intermediate risk (risk value = 0.3-0.7, with 2 factors or microcalcification) and low risk (risk value = 0.1-0.2, with 1 factor except microcalcification). In the validation dataset, the malignancy rate of thyroid nodules > 4 cm that were classified as high risk was 88.9%; as intermediate risk, 35.7%; and as low risk, 6.9%. The new model showed greater AUC than ACR TI-RADS (0.897 vs. 0.855, p = 0.040), but similar sensitivity (61.9% vs. 57.1%, p = 0.480) and specificity (91.5% vs. 93.2%, p = 0.680). Conclusion Microcalcification, solid mass, ill-defined border and hypoechogenicity on ultrasound may be signs of malignancy in thyroid nodules > 4 cm. A risk stratification model for nodules > 4 cm may show better diagnostic performance than ACR TI-RADS, which may lead to better preoperative decision-making.