The purpose of this study was to assess the relationships between the expression of SHP2 and VEGF, VEGFR-1, VEGFR-2, MMP-2, MMP-9, TIMP-1, TIMP-2, and microvessel density (MVD), as well as the clinicopathologic parameters of these markers in non-small cell lung cancer (NSCLC). Using a tissue microarray, the expression of these 8 markers in 80 NSCLC cases was detected by immunohistochemistry. The expression of the markers was higher in cancer tissues when compared with the surrounding tissues. The MVD was lower in the CD34-positive cancer tissues than in the surrounding tissues. Significantly higher positive rates of expression for SHP2, MMP-9, and MMP-2 were observed in patients with lymph node metastases. The later the clinical stage was, the higher the expression of MMP-9 and MMP-2. The expression of VEGF in patients with lung squamous cell carcinomas was significantly higher than in patients with lung adenocarcinomas. The positive expression of SHP2 correlated significantly with that of VEGFR-2 and the MVD and a survival disadvantage was noted in the patients with SHP2-positive tumors. Therefore, our data suggest that the expression of SHP2 in NSCLC has high specificity and sensitivity and is closely related to lymph node metastasis and the expression of VEGFR-2 and the MVD in patients with NSCLC. SHP2 expression may promote the invasion and metastasis of NSCLC through angiogenesis and the lymphatic system.