Rh immunization occurring during a first pregnancy with no history of preceding abortion or transfusion may result when Rh incompatible fetal to maternal bleeding ensues early enough in the gestation to initiate a maternal immune response before parturition. Alternatively, the initial antigenic stimulus could be the consequence of maternal to fetal transfer of Rh-in-compatible erythrocytes while the patient herself was in utero or at the time of her own delivery. These hypotheses were tested by I) analysis of the blood group and Rh of 22 Rh-immunized primigravidas, their infants, and their own mothers; 2) comparison of the number of fetal cells in the maternal circulation during the antepartum period in 20 women at high risk for fetal to maternal bleeding with their matched controls; and 3) Rho(D) antibody determinations in 70 Rh-negative infants born to Rh-positive mothers. The results indicate that antepartum fetal to maternal bleeding is the usual cause of Rh immunization in primigravidas, and the Rh-negative woman with blood group A, B, or AB who gestates an ABO compatiblc Rh-positive male is at highest risk. The antepartum use of anti-Rho(D) immune globulin has potential prophylactic value in this situation.