Objective Sickle cell disease (SCD) is remarkable for stress erythropoiesis. We investigated the progenitor populations contributing to erythroid stress. Materials and methods We characterized hematopoietic progenitor cells in sickle bone marrow and sickle peripheral blood from patients with SCD compared to those in normal bone marrow. Results There were increased proportions of sickle bone marrow and sickle peripheral blood CD34 + cells that coexpressed glycophorin A (GlyA), normally expressed late during erythroid differentiation when CD34 is down-regulated. Remarkably, increased numbers of CD34 +CD38 − hematopoietic progenitor cells from sickle bone marrow ( p < 0.03) and sickle peripheral blood ( p < 0.004) coexpressed GlyA, compared to normal bone marrow CD34 +CD38 − hematopoietic progenitor cells. At a molecular level, even the sickle bone marrow and sickle peripheral blood CD34 +CD38 − hematopoietic progenitor cells not expressing GlyA by fluorescence-activated cell sorting or reverse transcriptase-polymerase chain reaction expressed the erythroid-specific gene GATA-1, unlike normal bone marrow, suggesting desynchronized erythroid gene expression in the SCD hematopoietic progenitor cells. We also generated red blood cells in vitro from GlyA + and GlyA −CD34 + cells. GlyA +CD34 + produced more F cells ( p < 0.02) and had lower clonogenicity ( p < 0.01) and erythroid expansion potential. Increased F cells were generated only from sickle CD34 + hematopoietic progenitor cells ( p < 0.04), as occurs in vivo. Conclusion Stress erythropoiesis in SCD has been postulated to accelerate erythropoiesis and production of F cells. Thus, CD34 +CD38 − expressing GlyA may represent the “stress progenitor” population. This is the first study characterizing CD34 + and CD34 +CD38 − hematopoietic progenitor cells in sickle bone marrow, comparing them to sickle peripheral blood and normal bone marrow and using them to generate sickle red blood cells that recapitulate F cell production observed in vivo. We identified a unique population of GlyA +CD34 + cells in SCD, which is in an accelerated erythroid differentiation pathway, has not down-regulated CD34 antigen expression, and predominantly generates F cells.