Opsonin-independent macrophage phagocytosis was investigated as a possible mechanism of controlling early blood-stage Plasmodium chabaudi AS infection. Early during infection, peritoneal macrophages from resistant C57BL/6 (B6) mice exhibited increased phagocytosis of parasitized red blood cells (pRBCs) and free merozoites, which was absent in mice with deficient interferon (IFN)-gamma production during infection, including susceptible A/J, interleukin (IL)-12 p40, and IFN-gamma gene knockout mice. IFN-gamma treatment of macrophages collected from B6 and A/J mice early during infection enhanced phagocytosis of pRBCs, but IL-10 treatment inhibited this function. In vitro and in vivo studies in which type I and II class A scavenger receptor-deficient mice and inhibitors of scavenger and mannose receptors were used revealed that scavenger receptors other than class A type I and II and mannose receptors may play a role in malaria parasite uptake. These results indicate that opsonin-independent phagocytosis contributes to the IFN-gamma-dependent control of acute blood-stage malaria infection.