AbstractBackground:Transfusion of D+ red blood cells (RBCs) to D− recipients can be accidental or necessary due to D− RBC shortage. Alloimmunization can complicate future transfusions; implications for women of childbearing age are compounded by possible hemolytic disease of the fetus and newborn. Rh immunoprophylaxis is effective, and indicated, for preventing alloimmunization. Reports of massive D+ mismatch (e.g., in the case of fetal‐maternal bleed) are limited, and standard recommendations for managing these rare events are lacking. The cases discussed herein of women of childbearing age who suffered severe trauma requiring emergency surgery illustrate the dilemma of determining the ideal strategy for Rh immunoprophylaxis.Case reports:The first patient received two units of mismatched RBCs and was treated with intravenous Rh immune globulin (IV RHIG; Rhophylac®, CSL Behring, Kankakee, IL) monotherapy beginning 49 h postsurgery. For the second patient, who received three units of D+ RBCs, partial RBC exchange transfusion, followed 48 h later by IV RHIG, was deemed appropriate based on the large volume of RHIG needed and concerns of hemolytic transfusion reaction and hyperbilirubinemia. Both patients recovered in full without further intervention; the first patient delivered a healthy child ∼11 months posttreatment.Conclusions:Rh immunoprophylaxis is effective, and indicated, for preventing alloimmunization in women of childbearing age to protect the mother, fetus, and newborn. For the general population, a case‐by‐case approach is recommended. The availability of IV RHIG improves patient safety by facilitating the delivery of such treatment. RBC exchange should be considered for large volume mismatches. J. Clin. Apheresis, 2010. © 2009 Wiley‐Liss, Inc.