Objective: To investigate the surgical strategies for differentiated thyroid cancer (DTC) of the isthmus. Methods: The clinical data of 26 patients with isthmus DTC undergoing surgical treatment from January 2000 to January 2012 were retrospectively analyzed. Results: All of the 26 patients underwent total thyroidectomy with synchronous bilateral level VI lymph node dissection, and of them, 16 cases with deep cervical lymph nodes involvement received simultaneous uni- or bilateral functional/radical neck dissection. No surgical death occurred in the entire group of patients, unilateral superior laryngeal nerve injury occurred in 1 case, unilateral recurrent laryngeal nerve injury occurred in 2 cases, transient hypoparathyroidism occurred in 3 cases and permanent hypoparathyroidism occurred in 1 case. All of the 26 patients were followed up for one year to 12 years, and all were alive. Among them, 7 cases developed lateral neck recurrence and metastasis, and were treated by a second radical neck dissection plus 131I ablation. Conclusion: Total thyroidectomy with synchronous bilateral level VI lymph node dissection is an effective procedure for isthmus DTC, and functional/radical neck dissection should be done when the lateral neck node is involved. Anatomic familiarity and meticulous standardized operation are essentials for avoiding serious complications.