The objective of this study was to investigate complement activation in uncomplicated, early phases of human malaria. Fifteen healthy volunteers were experimentally infected with Plasmodium falciparum malaria. Parasitemia and complement activation products were assessed. During blood stage parasitemia, volunteers showed a significant increase in soluble terminal complement complex (TCC) formation. After start of a curative regimen of artemether/lumefantrine, TCC further increased due to activation of both the classical and the alternative pathway. In-vitro studies confirmed activation of complement by parasite cultures. We thus detected an increase in complement activation in volunteers with experimentally induced malaria, even before parasitemia could be detected microscopically. This significant increase in complement activation occurred despite the possible control of TCC formation by complement regulatory proteins on erythrocytes and the extremely low levels of parasitemia. Treatment with artemether/lumefantrine was followed by classical and alternative pathway complement activation, without evidence for mannan-binding-lectin-mediated complement activation.