Sickle cell disease (SCD) is a monogenic disorder with multi-organ involvement(1). Patients with SCD suffer from recurrent vaso-occlusive crisis (VOC) resulting from sickling of red blood cells, which is induced by polymerization of deoxy-sickle hemoglobin (HbS)(1,2). Fetal hemoglobin (HbF) can ameliorate symptoms of SCD by inhibiting deoxy-HbS polymerization(3). Hydroxyurea (HU) is approved by FDA for the treatment of SCD(4). It induces HbF synthesis through multifactorial and still not well understood mechanisms(4-7). However, approximately 5-15% of patients show no significant clinical improvement(8). Additionally, numerous patient and physician-related factors limit its utilization(9). Therefore, it is important to identify additional HbF-inducing therapeutic agents, particularly those that act by mechanisms different from HU to allow potential combination therapy in the future. Previously, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was shown to activate γ-globin gene transcription(10). Forced overexpression of PGC-1α in erythroid progenitors obtained from Lin- cells from SCD transgenic mice induces γ-globin expression(10), suggesting that PGC-1α represents a new molecular target for potential therapeutic intervention in treating SCD. In the present study, the effect of PGC-1α upregulation in primary human CD34+ derived erythroid cells was explored; an increase in γ-globin mRNA and the percent of F-cells was observed. Through literature search, ZLN005 and SR-18292 were identified as potential PGC-1α agonists(11,12). Both compounds increase the percentage of F-cells in primary human CD34+ derived erythroid cell culture. Combined treatment with HU led to a significantly higher increase in F-cell % than the increase observed under treatment with either HU, ZLN005 or SR-18292 alone. Results from those studies add to the understanding of PGC-1α and its effects on primary human erythroid cell differentiation, maturation, and HbF induction. Additionally, the results show proof of principle for combination therapy to treat SCD patients to ameliorate their disease severity by up-regulating HbF expression. Together, the knowledge gained through these studies is novel and will potentiate the development of a new class of compounds to induce HbF synthesis in adults.