Women are at increased risk from malaria during pregnancy, and, for unknown reasons, this risk is greatest during the first pregnancy. Plasmodium falciparum, the most virulent of the four malaria parasites of humans, adheres to a molecule called chondroitin sulphate A (CSA) on the surface of syncytiotrophoblasts (cells lining the intervillous space) and sequesters in the human placenta. Here we show that anti-adhesion antibodies, which limit the accumulation of parasites in the placenta, appear in pregnant women from Africa and Asia who have been pregnant on previous occasions (multigravidas), but not in those who are pregnant for the first time (primigravidas). Anti-adhesion antibodies against CSA-binding parasites are strain-independent and are associated with greatly reduced prevalence and density of infection. We conclude that malaria susceptibility in primigravidas is related to the lack of these anti-adhesion antibodies, and that an anti-adhesion vaccine for maternal malaria may be globally effective.