Objective: This study is to investigate the clinical value of ^99mTc-galacto-RGD2 SPECT/CT in the diagnosis of refractory thyroid carcinoma and correlation between radiouptake and integrin αvβ₃ expression in the tumor. Materials and methods: Twenty two patients were consecutively enrolled in this study, 7 patients with poorly differentiated thyroid carcinoma, 5 patients with anaplastic thyroid carcinoma and 10 refractory thyroid cancer which could not be completely removed by surgery, ^99mTc-galacto-RGD2 SPECT/CT was undertaken in all patients. ROI analysis was utilized for the quantitation of tumor uptake which was expressed as the ratio of tumor to normal tissue (T/NT). Final diagnosis was confirmed by histopathology and clinical follow-up. CD31 and integrin αvβ₃ expression was measured by immunohistochemistry assay. Results High contrast image could be acquired with ^99mTc-galacto-RGD2, regarding refractory thyroid cancer, no thyroxine withdraw is needed, all 22 patients showed focal uptake in the thyroid primary lesion and metastatic site. ^99mTc-galacto-RGD2 imaging showed 18 patients with 52 metastatic lymph nodule, 8 patients with 26 lung metastasis, 5 patients with 29 bone metastatic lesions. T/NT in the tumors was 11.45±2.56, significantly correlated with integrin αvβ₃ expression (r = 0.78, P < 0.05). Conclusion: ^99mTc-galacto-RGD2 have great potential for the diagnosis and response monitoring in refractory thyroid carcinoma and contribute to quantitate integrin αvβ₃ expression. Furthermore, RGD imaging might serve as a surrogate of proliferation and metastasis in refractory thyroid cancer. This study will shed light on integrin based theranostics in refractory thyroid carcinoma.