OBJECTIVE Some studies have found an increased prevalence of pregnancy-induced hypertension among women sharing HLA antigens with their spouses or fetuses, thus supporting the hypothesis that maternal sensitization to fetal HLA alloantigens reduces the risk for pregnancy-induced hypertension. However, not all studies have confirmed these findings. No investigators have examined the four different types of maternal-fetal HLA relationships in their studies of pregnancy-induced hypertension. Our goal was to examine such associations to test further the HLA-allosensitization hypothesis. METHODS We conducted a cohort study of pregnancy-induced hypertension among 683 nulliparous women. Women and their neonates were typed for HLA-A, -B, -DR, and -DQ antigens using serologic techniques to establish maternal-fetal relationships. RESULTS We found an increased prevalence of pregnancy-induced hypertension when the fetus, but not the mother, was potentially exposed to HLA-DR alloantigens (maternal allogenicity) compared with the other three conditions combined (P < .003). Controlling for confounding factors, the increased prevalence of pregnancy-induced hypertension persisted in situations of maternal HLA-DR allogenicity (P < .007). CONCLUSIONS Based upon our observations and other immunologic studies of pregnancy-induced hypertensive and uncomplicated pregnancies, we conclude that a maternal humoral response against fetal anti-HLA-DR immunoglobulin (IgG) antibody may influence the development of pregnancy-induced hypertension. This could occur when an immunocompetent fetus is exposed to maternal HLA-DR alloantigens, maternal exposure to fetal HLA-DR alloantigens alloantigens, maternal exposure to fetal HLA-DR alloantigens is not possible, and fetal IgG antibody bears paternally inherited markers allogeneic to the mother.