ZNF580, a newly found C2H2 zinc finger transcription factor, was first described by Zhang (GenBank ID: AF184939). Emerging evidence has suggested that reactive oxygen species (ROS) play an important role in redox-sensitive signal transduction, and the vascular endothelium plays a critical role in the vascular inflammatory response. In this communication, we present evidence for the potential role of ZNF580 in hydrogen peroxide (H2O2)-regulated inflammation-related signaling pathways. In a human endothelial cell hybridoma line (EA.hy926), ZNF580 levels were markedly upregulated with H2O2 stimulation in different concentrations (0-400 μM) and at different time-points (0-6 h). H2O2 promoted the rapid translocation of p65 from the cytoplasm into the nucleus according to immunocytochemistry staining. In subsequent research, inhibition of NF-κB by pyrrolidine dithiocarbamate (PDTC, a selective chemical inhibitor of NF-κB) was shown to block the upregulated expression of ZNF580 that was induced by H2O2. Furthermore, transient transfection of ZNF580 resulted in an increase of the pro-inflammatory cytokine interleukin-8 (IL-8) 3.01±0.05 folds according to real-time RT-PCR and ELISA assays, which also showed significantly enhanced motility of human acute monocytic leukemia cells (THP-1). These results suggest that H2O2 upregulates the expression of ZNF580 via the NF-κB signaling pathway, and overexpression of ZNF580 plays a critical role in augmenting the release of pro-inflammatory cytokine IL-8.