Background: Pregnant women are susceptible to P. falciparum infection during pregnancy resulting in placental malaria. Placental malaria is associated with the sequestration of malaria parasites in the placenta due to expression of VAR2CSA, (a member P. falciparum of erythrocytes membrane protein 1(PfEMP1) family) on the surface of the infected red blood cell. Antibody has been described before to be protective against malaria and pregnancy malaria has been previously associated with lack of immunity to VAR2CSA. We aimed to investigate the associations between opsonic phagocytosis of VAR2CSA expressing parasites and protection from placental parasitemia. Methods: Plasma samples were collected at 14-26 gestation weeks (gw) from pregnant women in Papua New Guinea. Samples were selected randomly of frequency matched groups (classified as Non-Infected, Infected but no placental malaria and Placental Malaria based on placental pathology and peripheral parasitemia at delivery). Phagocytosis assays were done using CS2 parasites (which express VAR2CSA) opsonised with plasma or purified IgG and the THP-1 cell line. Additionally, total IgG and IgG subclasses towards the surface of the CS2 infected erythrocyte were also quantified.Results and conclusions: Women who were infected but who did not have placental malaria at delivery had plasma at 14-26 gw which promoted high opsonic phagocytosis in comparison to plasma from women with placental malaria at delivery (P<0.0001). When looking at total IgG levels binding to the surface of the infected erythrocyte a similar result was also seen with IgG1,3 and 4 (P=0.01, P=0.01, P=0.03, respectively). In contrast, Phagocytosis of CS2 opsonised with purified IgG from these same samples was not associated with protection (P= 0.56). This is the first-time opsonic phagocytosis has been specifically associated with protection from placental parasitemia. The lack of association with purified IgG suggests that other factor in the plasma may play an important role in immunity against placental malaria.