Papillary thyroid cancer (PTC), one of the most common malignant thyroid tumors, exits widely in the thyroid of adolescents. Thyroid transcription factor 1 (TTF1) and 2 (TTF2) were thyroid-specific transcription factors, and regulated expression of the thyroid-specific genes. Hence, the aim of the present study was to evaluate the correlation between gene variants of TTF1 and TTF2 and the risk of PTC in Chinese population.Two tagging single-nucleotide polymorphisms (tSNPs) on TTF1 and TTF2 were selected and genotyped by matrix-assisted laser desorption/ionization time-of-flight (MALDITOF) mass spectrometry in a hospital-based case-control study of 297 PTC patients and 594 healthy controls. Furthermore, a meta-analysis of the association between TTF1 and TTF2 and PTC risk was also performed.We found that the rs944289 on the TTF1 was significantly associated with increased PTC risk (TT vs CC, OR = 1.53, 95% CI = 1.05-2.24; CT + TT vs TT, OR = 1.34, 95% CI = 1.00-1.79; T vs C, OR = 1.27, 95% CI = 1.04-1.55). Similarly, the rs965513 on the TTF2 can also elevate the risk of PTC significantly (GA vs GG, OR = 1.67, 95% CI = 1.07-2.59; AA+GA vs AA, OR = 1.37, 95% CI = 1.09-1.82; A vs G, OR = 1.29, 95% CI = 1.05-1.59). Furthermore, results of stratified analysis revealed that the risk effects of rs944289 and rs965513 were more overpowering in the subgroups of patients with MNG, as well as subjects without metastasis. Results of meta-analysis from the previous study and our new data indicated that variants of rs944289 and rs965513 might be the genetic susceptible factors both in Asians and Caucasians.We get the conclusion that mutations of TTF1 and TTF2 are significantly associated with an increasing risk of PTC in Chinese. However, more detailed investigations and further large-scale studies on genetic functions to provide more conclusive and accurate evidence are required in the future.