The course of malaria does not only depend on the virulence of the parasite Plasmodium, but as well on properties of the host cells. Here, we show that annexin A7-deficient mice (AnxA7(/() are partially protected from infection with Plasmodium berghei ANKA. AnxA7(/( mice developed less parasitaemia and partially survived, while wildtype mice all died from infection. Protection was conferred by accelerated phosphatidylserine exposure of infected AnxA7(/( erythrocytes resulting in their rapid clearance from circulating blood. Enhanced phosphatidylserine exposure of AnxA7(/( erythrocytes was triggered by an approximately tenfold increase of cellular prostaglandin E2 (PGE2) formation with subsequent activation of cation channels, Ca2+ entry, and Ca2+ sensitive scrambling of the cell membrane, events blunted in AnxA7+/+ erythrocytes. Similar to AnxA7(/( erythrocytes, human erythrocytes from sickle cell trait carriers (HbA/S erythrocytes) responded to P. falciparum infection with accelerated PGE2 formation, Ca2+ entry and phosphatidylserine exposure. In conclusion, phosphatidylserine exposure of Plasmodium-infected AnxA7(/( or HbA/S erythrocytes results in rapid clearance of these cells and confers partial protection against malaria.