BACKGROUND: Vascular endothelial growth factor (VEGF)-C and VEGF-D are novel growth factors that regulate lymphatic vessel growth. This study was designed to examine whether the expression of three VEGF family members, VEGF-A, VEGF-C and VEGF-D are associated with the clinicopathologic parameters, especially with lymph node metastasis, in advanced gastric carcinomas. METHODS: Immunohistochemical staining was performed for VEGF-A, VEGF-C, and VEGF-D in the surgically resected specimens from 102 patients with advanced gastric carcinoma. The mRNA expressions of the three VEGF family members were assessed in 16 cases of tumor tissues and their corresponding non-neoplastic tissues. RESULTS: Of the 102 gastric carcinomas, 74 (73%), 82 (80%), and 34 (33%) cases showed cytoplasmic immunoreactivity for VEGF-A, VEGF-C and VEGF-D, respectively. Both VEGF-A and VEGF-C expressions were associated with lymphatic invasion and lymph node metastasis (p<0.05), but the VEGF-D expression was not associated with them (p>0.05). In the tumor tissue, VEGF-C mRNA expression was greater, while VEGF-D mRNA expression was lower than in the nonneoplatic tissue adjacent to the tumor. CONCLUSIONS: VEGF-A and VEGF-C may play important roles for the lymphatic spread of gastric carcinoma. We suggest that neutralizing both VEGF-A and VEGF-C may be reguired to block lymph node metastasis.