Background: Pregnant women develop protective anti-VSA IgG1 and IgG3 when infected by Plasmodium falciparum. The major target of IgG from serum of infected pregnant women is VAR2CSA. Methods: In this study, ELISA was used to compare the level of VAR2CSA DBL5 epsilon- specific IgG subclasses at enrolment and at delivery in a cohort of pregnant women in Senegal. All antibody measures were analysed in relation to placental infection according to parity. Results: The results show an interaction between immune response to placental malaria and parity. A higher level of anti-DBL5 epsilon-IgG3 at enrolment and a higher increase between enrolment and delivery were found in primigravidae who presented with uninfected placenta at delivery in comparison to those who presented with an infection of the placenta. However, high antibody level at delivery was associated with the infection of the placenta in multigravidae. Conclusion: This high level of IgG3 in uninfected primigravidae suggests a protective role of these antibodies in this susceptible group, highlighting the importance of VAR2CSA in general and of some of its variants still to be defined, in the induction of protective immunity to pregnancy malaria.