Fetal hemoglobin (HbF) expression is partially governed by the trans-acting quantitative trait loci BCL11Aand MYBand a cis-acting locus linked to the HBBgene cluster. Our previous analysis of the Genotype-Tissue Expression database suggested that BCL2L1was associated with HbF gene expression. In erythroid progenitors from patients with sickle cell disease, BCL2L1messenger RNA (mRNA) levels were positively correlated with HBGmRNA and total HbF concentration (r2= 0.72, P= .047 and r2= 0.68, P= .01, respectively). Inhibition of BCL2L1 protein activity in HbF-expressing HUDEP-1 cells decreased HBGexpression in a dose-dependent manner. Overexpression of BCL2L1in these cells increased HBGexpression fourfold (P< .05) and increased F cells by 13% (P< .05). Overexpression of BCL2L1in erythroid progenitors derived from primary adult CD34+cells upregulated HBGexpression 11-fold (P< .05), increased F cells by 18% (P< .01), did not significantly affect cell differentiation or proliferation, and had a minor effect on survival. Although the mechanism remains unknown, our results suggest that BCL2L1is associated with HbF gene activation.