AbstractMalaria symptoms and pathology are initiated by invasion of host erythrocytes by Plasmodium merozoites in a complex process that involves interactions between parasite and host erythrocyte proteins. Erythrocyte invasion presents attractive targets for malaria vaccine and drug development. Recently it was observed that antibodies against PfMSA180 (PF3D7_1014100) are associated with protection from symptomatic malaria, suggesting that this protein is a target of naturally acquired protective antibodies. Here we characterize PfMSA180, a ~170 kDa merozoite surface antigen that is potentially involved in erythrocyte invasion. PfMSA180 synthesized by the wheat germ cell-free system was used to raise antibodies in rabbits. Growth inhibition assays revealed that parasite invasion is inhibited by antibodies to the PfMSA180 C-terminal region, which contains an erythrocyte-binding domain. Surface plasmon resonance analysis showed that PfMSA180 specifically interacts with human erythrocyte integrin associated protein (CD47), suggesting that PfMSA180 plays a role during merozoite invasion of erythrocytes. Polymorphism analysis revealed that pfmsa180 is highly conserved among field isolates. We show that naturally acquired PfMSA180-specific antibodies responses are associated with protective immunity in a malaria-exposed Thai population. In sum, the data presented here supports further evaluation of the conserved erythrocyte-binding C-terminal region of PfMSA180 as an asexual blood-stage malaria vaccine candidate.