Red blood cells infected with Plasmodium falciparum (iRBCs) have been shown to modulate maturation of human monocyte-derived dendritic cells (DCs), interfering with their ability to activate T cells. Interaction between Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and CD36 expressed by DCs is the proposed mechanism, but we show here that DC modulation does not require CD36 binding, PfEMP1, or contact between DCs and infected RBCs and depends on the iRBC dose. iRBCs expressing a PfEMP1 variant that binds chondroitin sulfate A (CSA) but not CD36 were phagocytosed, inhibited lipopolysaccharide (LPS)-induced phenotypic maturation and cytokine secretion, and abrogated the ability of DCs to stimulate allogeneic T-cell proliferation. CD36-and CSA-binding iRBCs showed comparable inhibition. P. falciparum lines rendered deficient in PfEMP1 expression by targeted gene knockout or knockdown also inhibited LPS-induced phenotypic maturation, and separation of DCs and iRBCs in transwells showed that inhibition was not contact dependent. Inhibition was observed at an iRBC:DC ratio of 100:1 but not at a ratio of 10:1. High doses of iRBCs were associated with apoptosis of DCs, which was not activation induced. Lower doses of iRBCs stimulated DC maturation sufficient to activate autologous T-cell proliferation. In conclusion, modulation of DC maturation by P. falciparum is dose dependent and does not require interaction between PfEMP1 and CD36. Inhibition and apoptosis of DCs by high-dose iRBCs may or may not be physiological. However, our observation that low-dose iRBCs initiate functional DC maturation warrants reevaluation and further investigation of DC interactions with blood-stage P. falciparum.Dendritic cells (DCs) are specialized antigen-presenting cells that regulate both innate and adaptive immune responses and play a critical role in the initiation of primary T-cell responses. To function effectively as antigen-presenting cells, they undergo a process of maturation, characterized by increased expression of costimulator, major histocompatibility complex and adhesion molecules, and secretion of proinflammatory cytokines (reviewed in reference 35). DC maturation is usually activated by pathogens through ligation of pattern recognition receptors, such as Toll-like receptors, but may also be initiated by inflammatory cytokines and endogenous signals of cellular damage (reviewed in references 29 and 34).It has been suggested that modulation of DC function by the malaria parasite Plasmodium falciparum contributes to both the delayed acquisition of antimalarial immunity as well as immunosuppression associated with acute malaria infection. Urban et al. (50,52) showed that red blood cells infected with P. falciparum (iRBCs) at 100 iRBCs per DC inhibit maturation of human monocyte-derived DCs and interfere with their ability to activate T-cell responses. Interaction between the parasite protein P. falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on the surfaces of iRBCs, and the DC scavenger receptor...