Endothelial cell protein C receptor (EPCR) plays important roles in the regulation of blood coagulation and inflammation. Activity of EPCR is markedly changed by ectodomain cleavage and released as soluble protein (sEPCR). EPCR can be shed from the cell surface, and this is mediated by tumor necrosis factor-${alpha}$ converting enzyme (TACE). Purpurogallin (PPG) plays an important role in inhibiting glutathione S-transferase and xanthine oxidase as well as effective in the cell protection of several cell types. Here, we investigated the effects of PPG on phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-${alpha}$ interleukin (IL)-1${eta}$ and on cecal ligation and puncture (CLP)-mediated EPCR shedding and underlying mechanisms. Human umbilical vein endothelial cells pretreated with PPG (0, 5, 10, 20 or $50{mu}g/mL$) for 6 h and exposed to PMA ($1{mu}m$) for 1 h, and CLP-operated mice were administrated with PPG. Data showed that treatment with PPG resulted in potent inhibition of PMA, TNF-${alpha}$ IL-1${eta}$ and CLP-induced EPCR shedding by suppression of TACE expression. In addition, PPG reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases 1/2, and c-Jun N-terminal kinase. These results suggest the potential for use of PPG as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding.