High-mobility group AT-hook 2 (HMGA2) is a nuclear protein involved in the differentiation and proliferation of epithelial-derived tumors and also considered to be involved in the growth and differentiation of various malignant tumors, including thyroid cancer. Immunohistochemistry (IHC) for HMGA2 has been reported to show diffuse positivity in several follicular thyroid carcinoma (FTC) cases. This study aimed to investigate whether positive immunohistochemical staining for HMGA2 in primary tumors can be used to predict the prognosis and detect prognostic factors in malignant thyroid tumors associated with metastatic recurrence in FTC. Formalin-fixed, paraffin-embedded (FFPE) resected specimens used for the IHC for HMGA2. The association of positive HMGA2 staining with metastasis and recurrence, along with the potential of HMGA2 as a prognostic marker of metastatic recurrence, was statistically determined. HMGA2 staining was positive in most malignant tissues, whereas benign tissues were unstained. HMGA2 staining of the marginal and invasive regions was observed in FTC tissues. The association of HMGA2 staining with metastasis and recurrence was significant (p = 0.018). Kaplan-Meier curves showed an association of negative HMGA2 staining with metastasis and disease-free survival (p = 0.090). Tumor size (>
4 cm) and wide invasion were also significant factors (p = 0.043, p <
0.002). The risk ratio without HMGA2 was significantly reduced by 30% compared to that with HMGA2. In primary tumors, positive HMGA2 staining can be used to predict prognosis in malignant thyroid tumors associated with metastatic recurrence in FTC and negative HMGA2 staining may indicate longer disease-free survival after surgery.