Erythropoietin (Epo) is an essential regulator of red blood cell production. While adult Epo synthesis occurs almost exclusively in kidney, extrarenal Epo synthesis has been described in liver and brain in response to hypoxia or anemia. We have used adenoviruses to express soluble ectodomains of the VEGF receptors (sVEGFRs) Flk1 and Flt1 in the circulation of mice, achieving high-level VEGF sequestration, potent conditional ablation of VEGF function in adult animals, and inhibition of tumor growth and angiogenesis (Kuo et al. PNAS (2001). 98: 4605). Intriguingly, adenoviral expression of soluble Flk1 or Flt1 ectodomains, or a recently described soluble receptor VEGF Trap, is associated with profound stimulation of erythropoiesis and polycythemia, with hematocrit as high as 75% from basal levels of ~45%, and elevation of plasma Epo levels. sVEGFR expression results in a profound >100-fold induction of hepatic erythropoietin synthesis while renal Epo production is completely repressed. This effect is specific for adenoviruses expressing soluble VEGF receptors and not other receptor ectodomains, does not require liver transduction or hypoxia, and is not affected by Ad Cre-induced deletion of the hepatocyte HIF-1a gene in HIF-1aflox/flox mice. Selective inhibition of hepatocyte-produced VEGF in Ad Cre-treated VEGFflox/flox mice is sufficient to re-activate hepatocyte Epo production, likely via hepatocyte × endothelium crosstalk. These data suggest VEGF may function physiologically to repress hepatic Epo synthesis, while VEGF blockade leads to de-repression of hepatic Epo production via a novel hypoxia- and HIF-1a-independent pathway.