Vascular endothelial growth factor (VEGF) is an angiogenic cytokine, which plays a major role in tumor angiogenesis. VEGF mRNA expression is controlled by hypoxia, growth factors and hormones through both transcriptional and post-transcriptional mechanisms. VEGF mRNA has a short half-life and its abundance is regulated by the binding of stabilizing (HuR, hRNP-L) and still uncharacterised destabilizing proteins to its 3'-untranslated region. Here, we report that the ACTH-regulated zinc-finger protein TIS11b and its homologs TIS11 and TIS11d interact with the 3'-untranslated region of VEGF mRNA and decrease its stability (half-life reduced from 130 to 60 min). Within the 2201 bp 3'-untranslated region of VEGF mRNA, we identified a 75 bp domain, containing two consensus AU-rich motifs, which binds TIS11b and mediates its destabilizing activity. Ribonucleoprotein (RNP) complex immunoprecipitation experiments allowed us to demonstrate that the interaction between TIS11b and VEGF 3'-untranslated region occurs in live cells. Knocking down TIS11b expression in primary adrenocortical cells with small interfering (si)RNAs clearly indicated that TIS11b participates in the control of both basal and, to a larger extent, ACTH-induced VEGF mRNA expression levels. TIS11b is the first VEGF mRNA-destabilizing protein identified so far and therefore appears as a new potential target in antiangiogenic therapies.