Infection with either HIV or malaria during pregnancy often results in adverse outcomes for mother and child. Co-infection further increases the risks of these events, which include maternal anemia and babies with low birth weight. The immunological bases for the increased susceptibility of HIV-infected mothers to malaria and for the effect of co-infection on mother-to-child transmission of HIV are areas of major importance in public health. In this article, we review current data about humoral and cellular responses to HIV-placental-malaria co-infection and present an immunological hypothesis to explain the epidemiological findings.