Altered expression of syndecan-2 (SDC2), a heparan sulfate proteoglycan, has been associated with diverse types of human cancers. However, the mechanisms by which SDC2 may contribute to the pathobiology of lung adenocarcinoma have not been previously explored. SDC2 levels were measured in human lung adenocarcinoma samples and lung cancer tissue microarrays using immunohistochemistry and real-time PCR. To understand the role of SDC2 in vitro, SDC2 was silenced or overexpressed in A549 lung adenocarcinoma cells. The invasive capacity of cells was assessed using Matrigel invasion assays and measuring matrix metalloproteinase (MMP) 9 expression. Finally, we assessed tumor growth and metastasis of SDC2-deficient A549 cells in a xenograft tumor model. SDC2 expression was upregulated in malignant epithelial cells and macrophages obtained from human lung adenocarcinomas. Silencing of SDC2 decreased MMP9 expression and attenuated the invasive capacity of A549 lung adenocarcinoma cells. The inhibitory effect of SDC2 silencing on MMP9 expression and cell invasion was reversed by overexpression of MMP9 and syntenin-1. SDC2 silencing attenuated NF-kappa B p65 subunit nuclear translocation and its binding to the MMP9 promoter, which were restored by overexpression of syntenin-1. SDC2 silencing in vivo reduced tumor mass volume and metastasis. These findings suggest that SDC2 plays an important role in the invasive properties of lung adenocarcinoma cells and that its effects are mediated by syntenin-1. Thus, inhibiting SDC2 expression or activity could serve as a potential therapeutic target to treat lung adenocarcinoma.