Background Thyroglobulin (Tg) is a marker of tumor recurrence during thyroid cancer follow-up. While helpful in the postoperative setting, the clinical significance of preoperative Tg measurements remains unclear. The aim of the study was to determine if preoperative Tg levels are indicative of underlying malignancy or burden of metastatic disease. Methods A retrospective review of a prospectively collected database at an academic medical center of all thyroidectomy patients with a measured preoperative Tg level was conducted. Patients were grouped by Tg level into quartiles for initial univariate analysis, followed by multivariable analysis of variance. Results Between 2007 and 2012, 611 patients met criteria. Quartile breakdown was as follows: ≤19 ng/mL, 19.1-54 ng/mL, 54.1-151 ng/mL, and >151 ng/mL. Patients' age and gender were equivalent. Hashimoto's thyroiditis was most common in the lowest Tg group (24% versus 11%-12%, P < 0.01). While cancer was more common in the low Tg, metastatic disease was most common in the high Tg group. Specimen weight increased with increasing Tg levels (P < 0.01). Body mass index, gland weight, cancer, and Hashimoto's and metastatic disease were entered into a multivariable analysis. Only gland weight and metastatic disease correlated with Tg levels (both P < 0.001). All patients with Tg > 5000 ng/mL had metastatic disease (n = 6). Conclusions Although preoperative Tg levels are not associated with a diagnosis of cancer, they are associated with the presence of metastatic disease. All patients with a Tg > 5000 ng/mL had significant disease burden. In patients with concern for metastatic disease, preoperative serum Tg may be a useful marker to aid decision making. © 2014 Elsevier Inc. All rights reserved.