Objective:To investigate the expression of vascular endothelial growth factor (VEGF)-C,VEGF-D and their receptor-3 (VEGFR-3) in patients with non-small cell lung cancer(NSCLC),and the relationship with lymphangiogenesis and lymph node metastasis and their clinicopathological significance. Methods:Forty specimens of the NSCLC and eleven benign pulmonary diseases were studied. The expressions of VEGF-C,VEGF-D,VEGFR-3,LVYVE-1 and Prox-1 protein in specimens of NSCLC and benign pulmonary diseases tissues were studied by immunohistochemical technique. Microlymphatic vessel density (MLVD) was counted. Results:①Among 40 cases of NSCLC,the positive rates of VEGF-C,VEGF-D and VEGFR-3 were 77.50%(31/40),67.50%(27/40)and 62.50%(25/40) respectively,which were significantly higher than those of the paraneoplastic and pulmonary benign diseases tissues(P < 0.01).②Significant correlations between VEGF-C and VEGFR-3(r=0.409,P=0.005),VEGF-D and VEGFR-3(r=0.492,P=0.000) expression were observed in NSCLC;while no correlation between VEGF-C and VEGF-D(r=0.256,P=0.093) was observed. ③The expressions of VEGF-C,VEGF-D and VEGFR-3 protein in NSCLC were not correlated with age,gender,site and dimension of lesion,types of histological and degree of differentiation,but correlated significantly with lymph node metastasis (P < 0.05) and PTNM stage(P < 0.05). ④In the center of NSCLC cancerous tissues among 40 cases,the microlymphatic vessel densities marked by LYVE-1 and Prox-1 were 4.22 ± 1.25 and 1.99 ± 1.49 respectively,which were significantly lower than those of the pulmonary benign diseases tissues(P=0.000). However,the MLVDs in cancerous invasive edge were significantly higher than those in the center of cancerous tissues and those in the pulmonary benign diseases tissues (P=0.000). The MLVDs in the positive VEGF-C,VEGF-D and VEGFR-3 groups were significantly higher than those in the negative groups (P < 0.05). MLVDs were correlated significantly with lymph node metastasis (P=0.000) and PTNM stage (P=0.000). Conclusion:Non-small cell lung cancer cells may secrete lymphangiogenetic growth factors VEGF-C,VEGF-D and their receptor VEGFR-3,which induce the growth of lymphatic vessel endothelium and lymphangiogenesis by VEGF-C,VEGF-D/VEGFR-3 signaling pathway,and further accelerate lymphatic metastasis of NSCLC. VEGF-C,VEGF-D and VEGFR-3 might be acted as molecular phenotypes of lymphangioghesis in NSCLC and important markers for evaluating lymphatic metastasis and prognosis in patients with NSCLC. As specific markers of lymphatic vessel endotheliocyte,LYVE-1 and Prox-1 could identify blood vessels and lymphatic vessels strictly and evaluate vascular system of tumor fairly exactly.