Cyclosporin A (CsA) is a hydrophobic cyclic peptide produced by a fungus. CsA is widely used as an immunosuppressive agent to inhibit the rejection of transplanted organs. CsA also exhibits an antiparasitic activity against Plasmodium, the microorganism responsible for malaria disease. This antimalarial activity is not completely understood yet. In this study, we have used Langmuir monolayers and atomic force microscopy to investigate the interaction of CsA with different lipids: phosphatidylcholines with different molecular packing, cholesterol, and sphingomyelin. We have shown that CsA inserts in all kinds of lipid monolayers but it has a marked preference for sphingomyelin monolayers. This preferential insertion of CsA within sphingomyelin-enriched membranes could explain the antimalarial activity of CsA. Indeed, the parasites need to produce a membrane network inside the erythrocytes, which allows for their proper development/multiplication by exchanging nutrients with the external medium. This membrane network is particularly enriched in sphingomyelin, so the preferential insertion of CsA in these bilayers may destabilize them, thereby inhibiting the development of the parasite.