In vitro human monocytes from normal blood donors ingest red blood cells infected with Plasmodium falciparum more efficiently than normal red blood cells (NRBC). The phagocytic activity of human monocytes for infected red blood cells (IRBC) is greatly enhanced by the addition of immune sera obtained from individuals living in areas with endemic malaria. In contrast, the addition of sera obtained from individuals recovering from a first infection, or pooled normal sera, does not result in increased phagocytosis of IRBC. The phagocytosis enhancing activity of immune sera is associated with the IgG fraction and IgG depleted sera do not stimulate phagocytosis. Enhanced immune serum mediated phagocytosis occurs as a result of opsonization of IRBC. This was demonstrated by experiments in which monocytes or IRBC were preincubated with immune serum prior to the phagocytic assay. The opsonic activity could be absorbed by IRBC but not by NRBC. The opsonization of IRBC and subsequent phagocytosis were also dependent on the stage of development of the intracellular parasite. IRBC containing schizonts and trophozoites were preferentially phagocytosed as compared with ring forms. The role of malaria induced surface alterations and/or malaria surface antigens in the opsonization of IRBC by immune sera is discussed. These experiments suggest that phagocytosis of P. falciparum IRBC by monocytes may play a role in the immune elimination of malaria infection in humans.