BACKGROUND : During P. falciparum infection, the binding of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to endothelial cells (EC) results in the sequestration of pRBC. Several receptors located on the endothelial cells, including intercellular adhesion molecule 1 (ICAM-1), CD36, and endothelial protein C receptor (EPCR), contribute to PfEMP1 adhesion to the microvasculature. PfEMP1, expressed on the surface of parasitized red blood cells (pRBC), is composed of cysteine-rich interdomain regions (CIDR) and Duffy binding-like (DBL) domains. CIDRα1 competitively binds to EPCR with activated protein C (APC) and impairs cytoprotective and anticoagulant effects by APC, which plays important roles in severe malaria (SM) pathogenesis such as cerebral malaria (CM) and severe malaria anemia (SMA). The strategy to inhibit EPCR binding to pRBC while concomitantly strengthen its binding to APC may be crucial in restoring disrupted protein C (PC) system’s function. The purpose of this study is to evaluate the association between malaria severity and the EPCR genotypes as well as with soluble EPCR (sEPCR), and the study also addresses the physiological relevance of EPCR genetic polymorphism. RESULTS : In this study, we conducted a meta-analysis on the eligible studies by comparing the frequency of EPCR rs867186-GG versus rs867186-GA and -AA genotype in SM, mild malaria (MM) or uncomplicated malaria (UM) patients and healthy individuals from Thailand, Uganda, Benin, Tanzania, and Ghana. We also determined the relationship between rs867186 genotype and sEPCR levels. Our results showed that the genotype rs867186-GG is higher in MM/UM than in SM patients. SM patients carrying the rs867186-GG genotype have higher plasma soluble EPCR (sEPCR) levels than in rs867186-AG and rs867186-AA carriers. MM/UM patients carrying the rs867186-AG genotype have significantly higher level of sEPCR compared to those carrying rs867186-AA. Similarly, the rs867186-GG is associated with high sEPCR level in healthy individuals. CONCLUSIONS : This meta-analysis demonstrates that pRBCs and EPCR interactions are associated with malaria severity, and treatments that block their binding via PfEMP1 CIDRα1 could be a potential therapy for SM.