AIM To prove anthrax lethal toxin (LeTx) blocks the mitogen activated protein kinases (MAPKs) activation by degrading the MAPK/ERK kinases (MEKs) to suppress vascular endothelial growth factor (VEGF) secretion. METHODS Human adult retinal pigmented epithelium (ARPE) cells were cultured and treated with normal glucose, high glucose or high glucose with LeTx for additional 24, 48 or 72h for viable cell count. Total RNA from the ARPE was isolated for reverse transcription polymerase chain reaction (RT-PCR). The conditioned medium of ARPE cells treated in different group for 48h was filtered and diluted to detect the concentration of VEGF by enzyme-linked immunosorbant assays. Evaluate the role of MEK/MAPK pathway in the secretion of VEGF by immunoblotting. RESULTS In this study, we proved high glucose induced activation of the MAPK extracellular signal-regulated kinase (ERK1/2) and p38 in the ARPE cell line was blocked by anthrax LeTx. LeTx also inhibited high glucose induced ARPE cell over proliferation. CONCLUSION LeTx suppressed high glucose induced VEGF over secretion in the ARPE cells, mainly through a post-translational mechanism.