Background: Thyroid cancer is a common malignant tumor of the endocrine system. Its incidence has increased continuously worldwide for the past three decades. With advanced sequencing technology, we discovered that GABRB2 gene is overexpressed in tumor tissues and closely associated with vertebrate nervous systems. However, its role in cancer remains unclear. Methods: We conducted a massively parallel whole transcriptome resequencing and a comprehensive analysis of matched papillary thyroid carcinoma (PTC) tumors and normal tissues in 19 patients. Results showed that GABRB2 expression was significantly upregulated in thyroid cancer. Forty-five pairs of tumors and normal tissues were subjected to reverse transcription polymerase chain reaction to validate previous findings. The specific functions of GABRB2 in PTC cell lines (BCPAP, TPC1, and KTC-1) transfected with small interfering RNA were determined through cell colony formation, Cell Counting Kit-8, Transwell migration, Transwell invasion, and apoptosis assays. The effect of DNA demethylation on this gene was also examined. Results: GABRB2 was remarkably overexpressed in primarily sequenced FTC tumors and validation cohort (T: N = 4.94 +/- 3.43:0.83 +/- 1.71, P < 0.001), and this observation was consistent with that in the TCGA cohort (T: N = 38.92 +/- 35.53:0.30 +/- 0.55, P < 0.001). GABRB2 overexpression was correlated with lymph node metastasis in both cohorts (P < 0.01). In vitro experiments revealed that GABRB2 down regulation significantly inhibited the colony formation, migration, and invasion of the three PTC cell lines. Conclusion: GABRB2 plays important tumorigenic functions and acts as a novel oncogene in PTC. 2017 Published by Elsevier Inc.