Cerebral aneurysm (CA) rupture is one of the leading causes of stroke death. Recent experimental studies suggest that the pathophysiology of CA is closely associated with inflammation. A transcription factor, Ets-1, has been shown to regulate vascular inflammation and remodeling in a physiological and pathological condition. The expression and role of Ets-1 in CA development has been investigated in this study. Ets-1 was expressed and activated mainly in vascular smooth muscle cells (VSMCs) in both experimentally induced rat CAs and human CA walls by immunohistochemistry, western blotting and enzyme-linked mobility shift assay. The downstream target of Ets-1 in CA development was identified by chromatin immunoprecipitation (CHIP) analysis. CHIP analysis revealed that Ets-1 transactivated monocyte chemoattractant protein-1 (MCP-1) expression in CA walls. Treatment with ets decoy oligodeoxynucleotides resulted in the prevention of CA enlargement, upregulation of MCP-1 expression and increase in macrophage accumulation in CA walls. In conclusion, Ets-1 mediates MCP-1 expression in VSMCs in CA walls, thus promoting the progression of CAs. Inhibition of DNA-binding activity of Ets-1 may lead to the prevention of human CA enlargement and rupture. Results of this study will provide us a clue to a novel therapeutic strategy for CAs. Gene Therapy (2010) 17, 1117-1123; doi:10.1038/gt.2010.60; published online 29 April 2010