The natural history of alloimmunization to the Pl^A1 platelet antigen is uncertain. We followed 50 Pl^A1‐negative pregnant women during pregnancy and for 6 months post‐partum in order to determine this natural history. The cohort of Pl^A1‐negative women was obtained by Pl^A1 typing 5000 women. Three Pl^A1‐negative women formed anti‐Pl^A1 antibodies during this prospective study, two in pregnancy and one in the immediate post‐partum period. All three Pl^A1 antibody producers were HLA‐DR3 positive, a histocompatibility phenotype that is strongly associated with alloimmunization to the Pl^A1 antigen. One of the three infants delivered to these mothers was thrombocytopenic (platelet count 9 x 10⁹/1). The remaining two infants had normal platelet counts at birth (160 and 174 x 10⁹/1). The HLA‐A1, ‐B8, ‐DR3 and ‐DRw52 phenotype frequencies in the group of Pl^A1‐negative women who did not form Pl^A1 antibodies (n= 47) was similar to that found in their husbands, and that expected in a normal Caucasian population. From our data we estimate that alloimmunization to the Pl^A1 antigen occurs in approximately one out of every 1000 pregnancies in a Caucasian population. It is important to recognize that not all pregnancies in which a mother has formed Pl^A1 alloantibodies will result in the delivery of a thrombocytopenic infant. These findings are relevant to programs designed to either prevent alloimmunization to the Pl^A1 antigen (through passive administration of anti‐Pl^A1 immunoglobulin to at‐risk Pl^A1‐negative mothers), or to identify women at risk of delivery of thrombocytopenic infants (by antenatal screening to detect women alloimmunized to the Pl^A1 antigen).