Background To enhance donor availability, almost half of hematopoietic progenitor cell transplants (HPCTs) cross ABO blood type boundaries. ABO‐incompatible HPCTs are well tolerated; however, there is an increased risk of delayed hemolysis in patients with minor and bidirectional ABO mismatches. Delayed hemolysis generally occurs 1 to 2 weeks after HPCT and is related to production of alloantibodies directed against recipient ABO red blood cell (RBC) antigens by passenger donor lymphocytes. One previous study has suggested that prophylactic RBC exchange in patients with minor and bidirectional ABO‐mismatched HPCT reduces the risks of severe immune hemolysis, but this recommendation is controversial. Study Design and Methods Herein we describe our experience using prophylactic RBC exchange in patients with minor and bidirectional ABO‐mismatched HPCTs who were deemed to be at high risk for immune hemolysis. We compare the group of patients that received prophylactic RBC exchange with a historical cohort of ABO‐mismatched patients who underwent HPCT without prophylactic RBC exchange. Results Our study suggests that prophylactic RBC exchange in minor and bidirectional ABO‐mismatched HPCT does not reduce severe immune hemolysis, nor does it improve 1‐year survival, the number of RBC units transfused after transplant, or length of hospitalization after HPCT. Conclusion This study failed to identify a clear role for selected prophylactic RBC exchange in patients who were deemed at risk for severe post‐HPCT immune hemolysis.