Background Maternal allergy confers stronger allergy risk (than paternal allergy) suggesting that maternal patterns of immune response can directly influence immune development in offspring. Women prone to allergic immune responses to allergens may also have altered immune responses to other antigens including fetal antigens.Objective This exploratory study examines relationships between maternal immune responses to fetal antigens and the subsequent risk of allergy.Methods Mononuclear cells (MNC) were collected from 36 mother-infant pairs to compare maternal (and fetal) cellular immune responses to alloantigens (fetal, maternal or unrelated donor [URD]), and allergens in allergic (18 pairs) and non-allergic (18 pairs) mothers. Thirty children had documented allergic outcomes at 6 years of age.Results In this population, allergic outcomes in the offspring were associated more strongly with materno-fetal immune interactions than with a maternal family history of allergy. Specifically, allergic disease at 6 years of age was associated with significantly higher maternal responses to fetal alloantigens (lymphoproliferation, P=0.008; IL-13, P=0.02 and IFN-gamma, P=0.015), whereas associations with maternal allergy did not reach significance (P=0.07). Fetal IFN-gamma alloantigen responses were significantly correlated with the degree of human lymphocyte antigen (HLA) mismatch (maternal HLA class II antibodies) (tau=0.3, P=0.03). The capacity of the fetus to produce IL-13 (tau=0.4, P=0.001) and IL-10 (tau=0.3, P=0.029) was directly related to the level of these cytokines produced by the mother in response to fetal antigens. Allergic mothers showed a non-significant trend for stronger lymphoproliferation to fetal alloantigens. The number of previous pregnancies (gravidity) was associated with stronger maternal responses to fetal alloantigens, as shown by lymphoproliferation (Kendall tau=0.3, P=0.04) and IFN-gamma (tau=0.3, P=0.04) synthesis, but did not affect fetal responses to the various stimuli.Conclusions Maternal responses to fetal antigens were related to fetal immune responses and subsequent allergy. This novel observation suggests that events at the materno-fetal interface have an important influence on early immune development and should be investigated further.