The CCAAT boxes of the β-like globin genes interact with three proteins: NF-Y, GATA-1 and NFE-6. We demonstrate that NFE-6 contains C/EBPγ, and address its role in globin gene regulation by erythroid overexpression of C/EBPγ, and a dominant-negative form C/EBPγΔB, in mice. Elevated levels of C/EBPγ, but not C/EBPγΔB, increase expression of the (fetal) γ-globin relative to the (adult) β-globin gene. Interestingly, fetal liver erythropoiesis is ablated when the C/EBPγ and C/EBPγΔB levels are further increased in homozygous transgenics. We suggest that targeted expression of dominant-negative leucine zipper proteins is a generally applicable approach to ablate specific tissues in mice.