Host defence proteins provide a valuable source of structures to guide the design of new generations of peptide drugs against pathogenic organisms. Human platelet factor 4 (PF4), released by activated platelets, can enter red blood cells (RBCs) infected with Plasmodium to kill malaria parasites. However, treatment with full-sized PF4 is not desirable due to toxicity induced by its intrinsic cytokine activity. PF4s antiparasitic activity has been identified as belonging to a C-terminal motif, with structural similarity to antimicrobial peptides (AMPs), where cationic amino acids are presented on one side of an a-helix and hydrophobic amino acids on the opposite side. These features are common in peptides with high affinity for membranes and promote strong interaction with lipid bilayers in cell membranes, particularly those with a high proportion of anionic phospholipids. We have engineered a novel cyclic peptide that mimics the structural presentation of the antiparasitic motifs of PF4, that is helical in physiological solutions and is resistant to degradation by serum proteases. It binds strongly and selectively to negatively charged phospholipids, particularly those containing phosphatidylserine-headgroups, which are exposed on the surface of Plasmodium-infected RBCs, but not in healthy RBCs. This correlates directly with the ability of the peptide to selectively enter infected RBCs and kill malaria parasites by lysing their intracellular digestive vacuole. The mode of action for our novel cyclic peptide is unique compared to traditional AMPs, as it enters RBCs without disrupting the host cell membrane. This provides an excellent platform for developing new peptide-based antimalarial drugs.