Objective: To assess the clinical application value of CD147 detection in thyroid nodules with nondiagnositic cytologic results from fine-needle-aspiration (FNA) biopsy. Methods: Patients with thyroid nodules admitted from October to December 2013 were selected, and their postoperative surgical specimens were used for FNA smear test. According to thyroid cytopathology results using the Bethesda reporting system, immunohistochemical staining for CD147 was conducted in 36 samples suspicious for malignancy; the CD147 positive cases were considered as malignant, and the results were compared with the postoperative pathological diagnosis of the paraffin sections. Results: Nineteen cases (52.78%) were considered benign and 17 cases were considered malignant by CD147 staining, while 16 and 20 cases were proven benign and malignant respectively by postoperative pathological examination. CD147 positive expression rate in malignant lesions was significantly higher than that in benign lesions (P<0.05). CD147 expression was associated with calcification of the thyroid nodules (CD147 positive rate was 89.47%) and lymph node metastasis (CD147 positive rate was 100%). The accuracy and sensitively of FNA plus CD147 immunochemical analysis for differential diagnosis of benign and malignant thyroid lesions was 91.67% and 85.0%, respectively. Conclusion: CD147 can be used as a molecular biological marker for thyroid cytopathologic diagnosis, and FNA biopsy combined with CD147 immunochemical analysis could improve the preoperative detection rate of thyroid cancer.