The angiogenic and lymphangiogenic vascular endothelial growth factor (VEGF)-D is the only member of the VEGF family that is not induced by hypoxia or by serum factors, but its induction is mediated by direct cell-cell contact. Here we show that VEGF-D mRNA is down-modulated either by beta-catenin mobilization from the cell membrane, by activation of the Wnt signaling pathway, or by transfection with the beta-catenin stable mutant. Down-modulation of beta-catenin by means of RNA interference showed an increase of VEGF-D mRNA steady state in fibroblasts. The beta-catenin-dependent decrease of VEGF-D mRNA is indirect and mainly due to reduced VEGF-D mRNA stability, as demonstrated by experiments of mRNA decay in the presence of transcription or translation inhibitors. By transient transfection of chimeric constructs carrying fusion of VEGF-D sequences under the control of the cytomegalovirus early promoter, we demonstrated that beta-catenin negative regulation is on the VEGF-D mRNA 3'-untranslated region. We mapped the VEGF-D mRNA-destabilizing element to a sequence, conserved between mouse and human VEGF-D, which contains an AU-rich element of group I. These results unveiled a new regulatory pathway for VEGF-D, which explains, at least in part, VEGF-D regulation in tumor progression.