Immune aplastic anemia (iAA) frequently results in transfusion dependence for platelets and packed red blood cells (PRBC), increasing the risk for complications. The most common immune mediated cause for platelet transfusion refractoriness is due to alloimmunization with human leukocyte antigen (HLA) antibody (Ab) to non-self class I antigens (Ag). The clinical impact of the HLA alloimmunization has not been well studied in patients with iAA. We investigated the clinical relevance of HLA alloimmunization in our large iAA patient cohort from 5 prospective trials, and its correlation with disease outcomes. Of 444 severe aplastic anemia (SAA) patients treated with immunosuppressive therapy (IST), 99 (22%) had HLA alloimmunization. Presence of HLA Ab was associated with shorter overall survival (OS), reduced responses to immunosuppressive therapy (IST) and higher risk of clonal evolution. Our data suggest that HLA alloimmunization is a marker of disease outcome. Furthermore, using single cell RNA sequencing, we show enhanced activation of both complement mediated pathways and the adaptive immune system in alloimmunized patients, indicating an interconnection between immune compartments.