E-cadherin (CDH1) is a tumor suppressor involved in epithelial cell-cell interactions. Single nucleotide polymorphisms (SNP) in the CDH1 gene, -160C/A and -347G/GA in the 5'-promoter region and +54C/T in the 3'-untranslated region (UTR) have been shown to be associated with tumor development and progression via modifying transcriptional activity, mRNA stability or protein expression. To investigate the influence of CDH1 SNP on susceptibility to esophageal squamous cell carcinomas (ESCC) and gastric cardia adenocarcinomas (GCA), a case-control study was conducted among 333 ESCC patients, 239 GCA patients and 343 controls from a northern Chinese population. CDH1 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. The results showed that; (i) genotypes with the +54C allele (C/C or C/T) significantly increased the risk of developing both ESCC and GCA compared to the +54T/T genotype (age and gender adjusted odds ratio [OR] = 1.45 and 2.28, 95% confidence interval [CI] = 1.06-1.99 and 1.58-3.30, respectively), and this association was significant only among non-smokers (OR = 1.68 and 2.64, 95% CI = 1.01-2.80 and 1.43-4.87 for ESCC and GCA, respectively), and individuals without a family history of upper gastrointestinal cancer (OR = 2.63 and 2.97, 95% CI = 1.36-5.10 and 95% CI = 1.32-6.68 for ESCC and GCA, respectively); (ii) compared with the -347G/G genotype, the -347GA and GA/GA genotypes significantly increased the risk of developing GCA (OR = 1.45, 95 % CI = 1.03-2.04); (iii) there was a significant association of CDH1-160C/-347G/+54C and -160C/-347GA/+54C haplotypes with the development of GCA, compared with the -160C/-347G/+54T haplotype (OR = 1.80 and 2.21, 95% CI = 1.33-2.44 and 1.43-3.42, respectively); and (iv) the influence of CDH1 SNP on the depth of tumor invasion and lymphatic metastasis in ESCC and GCA patients was not observed in this study. The present study indicates that CDH1 polymorphisms might modify susceptibility to ESCC and/or GCA.