Pure red cell aplasia (PRCA) is a potential complication after ABO-incompatible allogeneic hematopoietic stem cell transplantation (HCT). In case where PRCA persists beyond 60 days post-HCT, spontaneous resolution is rare, and therapeutic intervention is typically required. However, there is currently no established standard of care for its management. We report two cases of post-transplant PRCA that were refractory to conventional therapies, including erythropoietin and rituximab, and were successfully treated with daratumumab. These cases underscore the potential role of daratumumab as an effective therapeutic option in the management of PRCA following ABO-incompatible HCT. Given the limited data available on its use in this setting, our report contributes with valuable clinical evidence supporting its efficacy and safety.