Increasing evidence has demonstrated that beyond its role in activation of protein C, endothelial cell protein C receptor (EPCR) is involved in vascular inflammation. EPCR activity is markedly changed by ectodomain cleavage and released as the soluble EPCR. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-${alpha}$ converting enzyme (TACE). Cudratricusxanthone A (CTXA), a natural bioactive compound extracted from the roots of Cudrania tricuspidata Bureau, is known to possess hepatoprotective, antiproliferative, and anti-inflammatory activities. However, little is known about the effects of CTXA on EPCR shedding. Data from this study showed that CTXA induced potent inhibition of phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-${alpha}$, interleukin (IL)-$1{eta}$, and cecal ligation and puncture (CLP)-induced EPCR. CTXA also inhibited expression and activity of TACE induced by PMA in endothelial cells. In addition, treatment with CTXA resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate the potential of CTXA as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding.