Objective: To assess the significance of microcalcification under ultrasound in differential diagnosis between benign and malignant thyroid nodules and its relation with clinicopathologic features of papillary thyroid carcinoma (PTC). Methods: Seven-hundred and forty-three patients with thyroid nodules undergoing surgical treatment from May 2011 to November 2013 in Xiangya Hospital of Central South University were reviewed. The general data and results of preoperative ultrasound and postoperative pathology were analyzed. Results: Among the 743 cases of thyroid nodules, 137 cases (18.44%) were malignant nodules; 168 cases showed microcalcification, in which 81 cases (48.2%) were malignant nodules. The incidence of malignant nodules in cases with microcalcification was significantly higher than that of those without microcalcification (P<0.05). In cases with microcalcification, those with clustered microcalcification, predominantly solid nodules, blood-filled nodules and presence of lymph node calcification had increased incidence of thyroid cancer (all P<0.05). In PTC with microcalcification, the ratios of larger tumor size, thyroid capsule invasion and lymph node metastasis were increased (all P<0.05). Conclusion: Microcalcification of thyroid nodules under ultrasound has significant implication in differential diagnosis between benign and malignant thyroid nodules, which in combination with other ultrasonic features may further improve the diagnostic accuracy rate for thyroid cancer. PTC with microcalcification may relate to unfavorable clinicopathologic features.