Background: Papillary thyroid carcinoma (PTC) is the most common thyroid cancer, accounting for about 85 - 90%. Thyroglobulin (Tg) can be produced by normal thyroid follicular epithelial cells and well-differentiated malignant thyroid tumor cells. In our study, we investigated the correlation of preoperative serum Tg between benign thyroid tumors and PTC patients. Methods: The data of 1,074 patients were retrospectively collected, including benign thyroid tumor group (517 cases) and PTC group (557 cases). Preoperative serum Tg and other thyroid function indicators were detected by chemiluminescence immunoassay (CLIA). Serum levels were compared between patients with benign thyroid tumors and PTC using SPSS 22.0. Results: In patients with PTC, the levels of serum Tg were significantly lower than those in patients with benign thyroid tumors (p = 0.000). In both groups, no significant difference of serum Tg was observed between the genders, but there were significant differences of serum Tg among the different ages and tumor sizes. The results of Spearman correlation analysis showed that serum Tg positively correlated with tumor sizes and negatively correlated with serum thyroglobulin antibody (TgAb) in the two groups. Through the binary regression analysis, the independent predictors of PTC included the sex, tumor sizes, and serum TgAb of patients (p = 0.000, 0.000, and 0.020, respectively). For the PTC patients, serum Tg was markedly higher in the cervical lymph node metastasis (10.84 ng/mL), compared with no metastasis (8.41 ng/mL), with p = 0.017. Conclusions: Serum Tg in the PTC group was significantly lower than in the benign thyroid tumor group; however, serum Tg was not useful as an independent predictor of PTC patients. For the PTC patients, high preoperative serum Tg predicts the cervical lymph node metastasis.