Background: Thyroid surgery is one of the most common interventions in endocrine surgery. Thyroidectomy Difficulty Scale (TDS) was developed to identify more difficult operations, which correlate with long operative times, intraoperative problems and high complication rates. Objective: To identify clinical, biochemical and pathological parameters this can predict difficult thyroidectomy preoperatively. Patients and methods: This prospective study was randomized, non-interventional uncontrolled cross-sectional one. It was conducted on sixty patients. Those patients were already diagnosed to have thyroid disease needing thyroidectomy. Four items were used to score the difficulty of thyroid operations. Patient and disease factors were recorded for each patient. Difficult group and non-difficult groups were compared. Results: A total of 60 patients were scored using that scale. Of them, 46 suffered from hyperthyroidism, 13 from Hashimotos, and 11 from thyroid cancer. Patients were with hyperthyroidism, level of antithyroglobulin antibodies for them was>4 IU/ml, and high thyroglobulin (>150 ng/mL) may associated with difficult thyroidectomy. Conclusion: According to thyroidectomy difficulty scale, patients diagnosed as hyperthyroidism, increase of serum thyroglobulin, and antithyroglobulin antibodies preoperatively were associated with difficult thyroidectomy. This scale could assist surgeons in prediction of difficult operations and prepare for them.