Abstract: Objective To investigate the promoter methylation of Wif-1 and the protein expression of VEGF-C and VEGF-D in gastric cardia adenocarcinoma (GCA) and normal mucosa. Methods A nested MSP method was applied to examine the CpG methylation of the Wif-1 in tumors and corresponding normal mucosa. Immunohistochemistry was used to determine the protein expression of VEGF-C and VEGF-D. Results The frequency of Wif-1 gene promoter methylation in GCA and corresponding normal mucosa were 61.7% and 34.0%, respectively. The frequency of Wif--1 gene promoter methylation in GCA was higher than that in normal mucosa (P=0.000). The positive rate of VEGF-C, VEGF-D were 63.8% and 76.6% in the GCA tissues， which were significantly higher than those in normal mucosa (P=0.000). The protein expression of VEGF-C and VEGF-D in methylated GCA tissues were higher than those in unmethylated tissues (P_VEGF-C=0.008；P_VEGF-D=0.022). Furthermore, the methylation frequency of Wif-1 gene was correlated with invasion depth and lymphatic metastasis (P<0.05), but not with pathology classification. Conclusion Promoter methylation of Wif-1 and the higher expression of VEGF-C, VEGF-D may contribute to pathogenesis of GCA.