Otherwise clinically immune women in areas endemic for malaria are highly susceptible to Plasmodium falciparum malaria during their first pregnancy. Pregnancy-associated malaria (PAM) is characterized by placental accumulation of infected erythrocytes that adhere to chondroitin sulfate A (CSA). Susceptibility to PAM decreases with increasing parity, apparently due to acquisition of antibodies directed against the variant surface antigens (VSAs) that mediate the adhesion to CSA (VSA(CSA)). This study found that levels of VSA(CSA)-specific antibodies depend on endemicity, that anti-VSA(CSA) IgG is acquired during gestation week 20, and that plasma levels of the antibodies decline during the postpartum period. There is evidence that VSA(CSA)-specific antibodies are linked to placental infection and that high antibody levels contribute to the control of placental infection by inhibiting parasite adhesion to CSA. Data suggest that VSA(CSA) is a target for vaccination against PAM.