Background A Thyroidectomy Difficulty Scale (TDS) was previously developed that identified more difficult operations, which correlated with longer operative times and higher complication rates. The purpose of this study was to identify preoperative variables predictive of a more difficult thyroidectomy using the TDS. Methods A four item, 20-point TDS, was used to score the difficulty of thyroid operations. Patient and disease factors were recorded for each patient. Difficult thyroidectomy and non-difficult thyroidectomy (NDT) patients were compared. A final multivariate logistic regression model was constructed with significant (P < 0.05) variables from a univariate analysis. Results A total of 189 patients were scored using TDS. Of them, 69 (36.5%) suffered from hyperthyroidism, 42 (22.2%) from Hashimotos, 34 (18.0%) from thyroid cancer, and 36 (19.0%) from multinodular goiter. Among hyperthyroid patients, the DT group had a greater number preoperatively treated with Lugols potassium iodide (81.6% DT versus 58.1% NDT, P = 0.032), presence of ophthalmopathy (31.6% DT versus 9.7% NDT, P = 0.028), and presence of (>4 IU/mL) antithyroglobulin antibodies (34.2% DT versus 12.9% NDT, P = 0.05). Using multivariate analysis, hyperthyroidism (odds ratio [OR], 4.35, 95% confidence interval [CI], 1.23-15.36, P = 0.02), presence of antithyroglobulin antibody (OR, 3.51, 95% CI, 1.28-9.66, P = 0.015), and high (>150 ng/mL) thyroglobulin (OR, 2.61, 95% CI, 1.06-6.42, P = 0.037) were independently associated with DT. Conclusions Using TDS, we demonstrated that a diagnosis of hyperthyroidism, preoperative elevation of serum thyroglobulin, and antithyroglobulin antibodies are associated with DT. This tool can assist surgeons in counseling patients regarding personalized operative risk and improve OR scheduling. © 2014 Elsevier Inc. All rights reserved.