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Background: Thyroid nodules are common, but only 5% of nodules are found to be malignant. In North America, the incidence of thyroid cancer is increasing. Fine needle aspirate (FNA) biopsy is the diagnostic test of choice. Unfortunately, up to 20% of FNAs are non-diagnostic. A specific molecular marker for thyroid cancer is desirable. Evidence suggests that cell signaling through transforming growth factor beta (TGF-β) is important in the development of thyroid cancer. We sought to compare the expression of TGF-β in malignant and benign thyroid nodules., Methods: From 2008-present, thyroid nodule tissue from thyroidectomy specimens was prospectively collected and stored at -80°C. RNA extraction and reverse transcription was performed on 47 samples (24 papillary thyroid cancer and 23 benign nodules). Quantitative PCR using SYBR green was performed to detect TGF-β-1 and -2. Resulting CT values were normalized against β-actin. Gene expression was calculated using the 2(-ΔC)T method., Results: A significantly greater expression of TGF-β1 (p < 0.0001) was detected in the group of malignant thyroid nodules compared to benign nodules. There was no difference in the expression of TGF-β2 (p = 0.4735) between the two groups., Conclusions: In this study, we demonstrated that expression of TGF-β1 but not TGF-β2 is significantly increased in papillary thyroid cancer compared to benign thyroid nodules. This may serve as a potential diagnostic marker for papillary thyroid cancer.