Infection with Plasmodium species affects nearly 200 million annually with ~600,000 fatalities [1]. The clinical manifestation of the infection ranges from severe anemia, respiratory distress and cerebral malaria [2–4]. Infection with Plasmodium falciparum (Pf) is responsible for most of the fatalities associated with cerebral malaria and the survivors are often afflicted with long-term neurological problems and cognitive impairment [5]. The primary cause of death in the Pf-mediated cerebral malaria has been attributed to brain swelling, inflammation and perivascular edema resulting from the blood-brain barrier breakdown [3]. Upon entering circulation, Pf invades its host red blood cells and expresses hundreds of proteins as an essential process for maintaining viability and virulence [1]. One of these proteins, Pf Erythrocyte Membrane Protein 1 (PfEMP1) has been shown to bind endothelial protein C receptor (EPCR), thereby inhibiting the protein C anticoagulant and antiinflammatory pathways [6,7]. Another Pf secretory protein that modulates immune responses and coagulation is a histidine rich protein called HRPII [1,4,8]. HRPII is synthesized by Pf during asexual growth cycle in infected red blood cells and released upon their rupture [1]. The physiological role of HRPII is not known, though it has been hypothesized that it may be involved in detoxifying free heme released after hemoglobin degradation and in binding host glycosaminoglycans (GAGs) [1]. A recent study evaluating the effect of HRPII on blood coagulation discovered that HRPII specifically binds to some anticoagulant GAGs including heparan sulfate and dermatan sulfate [9]. Thus, HRPII was shown to effectively inhibit the cofactor function of high molecular weight heparins in inhibition of coagulation proteases, including factor Xa and thrombin, by antithrombin (AT) in in vitro assays [9]. Given its ability to bind anticoagulant heparins, it has been hypothesized that HRPII, released by the Pf-infected erythrocytes, can bind to GAGs in the microvasculature to prevent their interaction with AT, thereby contributing to coagulopathy associated with parasite infection [9,10]. Moreover, it was demonstrated that HRPII through activation of the inflammasome decreases the integrity of tight junctions and increases endothelial permeability, supporting the hypothesis that HRPII is a virulence factor that may contribute to cerebral malaria by disrupting the blood-brain barrier [8]. Recent results have indicated that AT elicits potent antiinflammatory signaling responses in vascular endothelial cells in response to cytokines and other proinflammatory stimuli [11–14]. The antiinflammatory activity of AT is mediated through the basic residues of the D-helix of the serpin binding to 3-OS containing vascular GAGs [15]. It has been demonstrated that the interaction of AT with vascular GAGs initiates antiinflammatory responses by inducing prostacyclin production that culminates in the inhibition of NF-κB activation, down-regulation of the expression vascular cell adhesion molecules and inhibition of the barrier-disruptive effects of proinflammatory cytokines [11–14,16]. In light of the findings that the Pf-derived HRPII can bind heparan sulfates to inhibit their cofactor activity in the AT-dependent inhibition of coagulation proteases together with the observation that HRPII may function as a virulence factor to contribute to cerebral malaria by compromising endothelial barrier integrity within the central nervous system, we hypothesized that HPRII counteracts the GAG-dependent antiinflammatory function of AT. To address this question, we expressed HRPII and evaluated its vascular activity in both cellular and animal models. The results demonstrate that a low concentration of HRPII is highly barrier-disruptive in vascular endothelial cells. In agreement with our hypothesis, HRPII effectively competes with AT for binding vascular GAGs. Moreover, we discovered that polyphosphates (polyP) bind HRPII with a high affinity to promote the inflammatory function of HRPII. This finding may have pathophysiological significance since it is known that Pf stores large amounts of short- and long-chain polyP’s in different blood stages of the infection [17].