BACKGROUND: The association between autoimmune thyroiditis (AIT) and thyroid cancer is still not clear despite many previous reports. This study investigated whether serologic thyroid antibodies are predictive of thyroid cancer in patients with thyroid nodules. METHOD: We retrospectively reviewed records of patients with thyroid nodules evaluated by ultrasonography-guided fine-needle aspiration cytology at our institution between January 2006 and December 2008. Thyroid autoimmunity was assessed by measuring thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb). The final outcome deciding a benign or malignant status involved a combination of cytology and histology. RESULTS: Of the 1638 patients, malignant nodules had a higher rate of positive TgAb (30.8% vs. 19.6%; p < 0.001) and elevated thyrotropin (TSH) levels (2.5 +/- 2.8 mIU/L vs. 2.1 +/- 2.0 mIU/L; p = 0.021) than benign nodules. The rate of positive TPOAb was not higher in malignant nodules, although both TPOAb and TgAb were well correlated with TSH levels and histological AIT. In the multivariate analysis, a positive TgAb was significantly associated with thyroid cancer (odds ratio [OR] = 1.61, 95% confidence interval [CI] 1.12-2.33) with upper tertile of normal range of TSH levels (OR = 1.72, 95% CI 1.12-2.63) and above normal range of TSH levels (OR = 1.98, 95% CI 1.06-3.70). CONCLUSION: We report for the first time that a positive serum TgAb test was an independent predictor for thyroid malignancy in thyroid nodules along with serum TSH levels regardless of the presence of AIT. Our results suggest that TgAb measurement could give additional information for predicting malignancy in cytologically indeterminate thyroid nodules in conjunction with clinical risk factors and TSH levels.