Spontaneous binding of infected erythrocytes to uninfected erythrocytes to form rosettes is a property of some strains of Plasmodium falciparum that is linked to severe complications of malaria. Curdlan sulfate (CRDS) is a sulfated glycoconjugate compound that is chemically similar to known rosette-inhibiting drugs such as heparin. CRDS has previously been shown to have antimalarial activity in vitro and is safe for clinical use. Here we show that CRDS at therapeutic levels (10 to 100 g/ml) significantly reduces rosette formation in vitro in seven P. falciparum laboratory strains and in a group of 18 African clinical isolates. The strong ability to inhibit rosetting suggests that CRDS has the potential to reduce the severe complications and mortality rates from P. falciparum malaria among African children. Our data support further clinical trials of CRDS.Despite decades of research, malaria still claims an estimated 1 million lives per year in sub-Saharan Africa, and severe complications, such as cerebral malaria, remain relatively common (19). Treatment for malaria involves the use of antimalarial drugs that kill the parasite, along with supportive measures, such as the provision of intravenous fluids and blood transfusion as required. Progress in understanding the pathogenesis of malaria has led to the possibility of designing therapies that target factors that contribute to severe disease in order to ameliorate the clinical complications and reduce the number of deaths from malaria.Rosetting is the spontaneous binding of noninfected erythrocytes to erythrocytes infected with mature asexual bloodstage Plasmodium parasites (reviewed in reference 14). In Plasmodium falciparum malaria, rosetting is associated with high levels of parasitemia (16) and with disease severity in African children (13,17), especially cerebral malaria (2). Other Plasmodium species also rosette, although it is only in P. falciparum that rosetting is linked to severe disease, probably because of the additional cytoadhesion properties that may act in concert with rosetting to cause microvascular obstruction (8,14). Rosetting in P. falciparum is mediated by heterogeneous mechanisms involving specific members of the parasite variant antigen family PfEMP1 (15), which are expressed on the surface of infected erythrocytes and which binding to a variety of receptors on uninfected red cells, such as complement receptor 1 (CR1), heparan sulfate-like sugars, and ABO blood group oligosaccharides (reviewed in reference 14).Previous work has shown that rosettes can be disrupted by sulfated glycoconjugate compounds such as heparin and fucoidan (1, 12), but the anticoagulant effects of these drugs prevent their use as treatments for severe malaria (19). Curdlan sulfate (CRDS; a semisynthetic sulfated 133-␤-D-glucan) has been shown to inhibit P. falciparum invasion in vitro (6) and is safe for use by adult patients with severe malaria (5). It was hypothesized that CRDS might be effective against P. falciparum rosetting (5) because of the chemical similari...