The identification of molecular markers allowing to differentiate between benign and malignant thyroid tumors remains a diagnostic challenge. Herein, we have used the expression of the high mobility group protein gene HMGA2 and its protein, respectively, as a possible marker detecting malignant growth of thyroid tumors. HMGA2 belongs to the high mobility group proteins, i.e. small, highly charged DNA-binding proteins. While HMGA2 is highly expressed in most embryonic tissues, its expression in adult tissues is very low. However, a reactivation of HMGA2 expression has been described for various malignant tumors and often correlates with the aggressiveness of the tumors. The aim of this study was to investigate whether the HMGA2 expression can be used to detect malignant thyroid tumors. RNA from 64 formalin-fixed paraffin-embedded thyroid tissues including normal tissue (n = 3), thyroiditis (n = 2), and follicular adenomas (n = 19) as well as follicular (n = 9), papillary (n = 28), and anaplastic (n = 3) carcinomas was reverse transcribed. Finally, real-time quantitative RT-PCR was performed. Expression differences of up to 400-fold were detected between benign and malignant thyroid tumors. Based on HMGA2 expression alone, it was possible to distinguish between benign and malignant thyroid tissues with a sensitivity of 95.9% and a specificity of 93.9%. There was a highly significant (P < 0.001) difference with histology of the tumors being the gold standard between the benign lesions and malignant tumors. Our results show that even as a stand-alone marker HMGA2 expression has a high potential to improve diagnoses of follicular neoplasms of the thyroid.