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Background: The presence of microcalcification is highly suggestive of malignancy; however, the association of macrocalcification with cancer remains unclear and controversial. The purpose of this study was to evaluate the diagnostic yield and accuracy of ultrasound (US)-guided fine-needle aspiration (FNA) of thyroid nodules with macrocalcifications and to investigate the association between macrocalcification subtype and malignancy risk., Methods: We retrospectively reviewed sonographic findings and pathologic results of thyroid nodules with macrocalcification in patients who underwent US-guided FNA in our hospital from January 2009 through December 2010. Inclusion criteria were as follows: (i) malignant or benign nodules confirmed on histologic examination of surgical specimens after US-guided FNA and (ii) nodules not histologically confirmed that were subjected to FNA at least twice and follow-up US examinations for 2 years. Thyroid nodules with macrocalcification were classified into four groups: smooth total (eggshell) calcification, smooth partial calcification, irregular calcification, and nodular calcification. The diagnostic yield of FNA for thyroid nodules with macrocalcification was determined by cytology. Sensitivity, specificity, and diagnostic accuracy of preoperative FNA cytology were calculated and compared with those of histologic examination of surgical specimens., Results: There were 188 nodules with macrocalcification in 167 patients; of these, 95 were benign, 80 were malignant, and 13 were nondiagnostic. The diagnostic yield of FNA for thyroid nodules with macrocalcification was 93.08%. Sensitivity, specificity, positive predictive value, and negative predictive value were 98.51%, 90.91%, 95.65%, and 96.77%, respectively. The false-positive value and false-negative value were 9.09% and 1.49%, respectively. The diagnostic accuracy was 96%. There was no statistically significant difference in the association between macrocalcification subtype and malignancy risk (p > 0.05)., Conclusions: Macrocalcification associated with thyroid nodules is not a reliable criterion for malignancy. FNA of thyroid nodules with macrocalcification had a high diagnostic yield and a reliable accuracy. Consistency between cytology and histology was almost perfect. Therefore, FNA is a good screening method for malignancy of thyroid nodules with macrocalcification.