The aim of this study is to investigate the associations between E-cadherin gene (CDH1) polymorphisms and papillary thyroid carcinoma (PTC) risk predisposition. We undertook a case-control study to analyze three CDH1 polymorphisms (+54T>C, -160C>A, and -347G→GA) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 98 patients with PTC and 176 control participants, and performed CDH1 genotyping using DNA sequencing. The obtained results indicated that overall, no statistically significant association was observed in +54T>C. Nevertheless, -347G→GA genotype was at increased risk of PTC (P = 0.001; odds ratio (OR) = 2.12, CI 95%:1.24-3.34). Furthermore, -347GA/GA genotype thyroid cancers were more significantly common in patients with tumor size of ≥20 mm than G or G/GA genotypes PTC and in cases of advanced T stage. However, -160C>A genotype demonstrated a protective effect in PTCs (P = 0.006; OR = 0.59, CI 95%: 0.42-0.87). These findings led us to conclude that polymorphism in -347G→GA was observed to be associated with susceptibility of PTC. However, -160C>A polymorphism indicated to play a protective role in susceptibility to PTC. Nevertheless, further investigation with a larger sample size is needed to support our results.