BACKGROUND AND OBJECTIVES: Angiogenesis is the main cause of lung adenocarcinoma (LAC) poor prognosis. This study aimed to investigate the effect of sex-determining region Y-box protein 5 (SOX5) expression on angiogenesis of LAC and explore its possible mechanism. PATIENTS AND METHODS: The effect on angiogenesis was tested by tube formation assays using human umbilical vein endothelial cells cocultured with A549 cells. Lentivirus shRNA of SOX5 and lentivirus of SOX5 overexpression system were used to establish LAC cell lines, which expressed SOX5 of different levels. SOX5 downstream signaling targets were analyzed by real-time qPCR and Western blot. We collected 90 LAC cases and the tissues were examined by immunohistochemistry for SOX5 and vascular endothelial growth factor (VEGF). RESULTS: We found that SOX5 overexpression in A549 cells significantly promoted tube formation capacity of the cocultured human umbilical vein endothelial cells. SOX5 increased VEGF expression and signal transducer activator of transcription 3 phosphorylation; however, SOX5 had no effect on extracellular signal-regulated kinase and protein kinase B pathway. Furthermore, the expression of SOX5 and VEGF had a significantly positive correlation (r=0.399, P=0.001) according to the tissue microarray data. CONCLUSION: These findings suggest that SOX5 induces angiogenesis by activating signal transducer activator of transcription 3/VEGF signaling and confer its candidacy as a potential therapeutic target in LAC.