Objective: To investigate the clinical features and principles for the diagnosis and treatment of nodular goiter with differentiated thyroid cancer. Methods: The clinical data of 47 patients with differentiated thyroid cancer in nodular goiter admitted from October 2003 to October 2011 were retrospectively analyzed. Results: All of the patients presented with neck mass or neck enlargement, and preoperative B ultrasound showed that 19 cases (40.43%) had small sand-like calcification in the thyroid nodules. The 47 patients underwent surgical treatment and were diagnosed to have differentiated thyroid cancer by postoperative pathological examination (36 cases of papillary carcinoma, accounting for 76.60% and 11 cases of follicular carcinoma, accounting for 23.40%). The surgical procedures performed included total ipsilateral lobectomy and isthmectomy plus level VI lymph node dissection, bilateral lobectomy and isthmectomy plus level VI dissection, and modified radical neck dissection that was additionally performed in cases with positive cervical lymph nodes. All patients received levothyroxine treatment after operation. These 47 patients were followed up for 6 to 36 months with average of (15.6±8.9) months after operation. Three cases developed recurrence within 16 to 33 months after operation and all underwent successful re-operation. No death occurred in the entire group. Conclusion: The preoperative diagnosis of nodular goiter with thyroid cancer is often difficult, for which preoperative ultrasound can provide useful information, and the pathological examinations of intraoperative fast frozen-section are critical for increasing the detection rate of thyroid cancer. The individualized, meticulous and standardized surgical treatment can provide a better prognosis for patients with concomitant nodular goiter and differentiated thyroid cancer.