Proliferation of the cyst lining epithelial cells is an integral part of ADPKD cyst growth. Cytokines and growth factors within cyst fluids are positioned to induce cyst growth. Vascular endothelial growth factor (VEGF) is present in ADPKD liver cyst fluids (human: 1,128 ± 78 pg/ml; mouse: 2,787 ± 136 pg/ml) and, to a lesser extent, in ADPKD renal cyst fluids (human: 294 ± 41 pg/ml; mouse: 191 ± 90 pg/ml). Western blotting showed receptors for VEGF (VEGFR1 and VEGFR2) were present in both normal mouse bile ducts and pkd2(WS25/-) liver cyst epithelial cells. Treatment of pkd2(WS25/-) liver cyst epithelial cells with VEGF (50 to 50,000 pg/ml) or liver cyst fluid induced a proliferative response. The effect on proliferation from liver cyst fluid was inhibited by SU5416, a potent VEGF receptor inhibitor. Treatment of pkd2(WS25/-) mice between 4 and 8 months of age with SU5416 markedly reduced the cyst volume density of the liver (Vehicle: 9.9 ± 4.3 % of liver; SU5416: 1.8 ± 0.7 % of liver). SU5416 treatment between 4 and 12 months of age markedly protected against increases in liver weight (pkd2(+/+): 4.8 ± 0.2 %BW; pkd2(WS25/-)-Vehicle: 10.8 ± 1.9 %BW; pkd2(WS25/-)-SU5416: 4.8 ± 0.4 %BW). The capacity of VEGF signaling to induce in vitro proliferation of pkd2(WS25/-) liver cyst epithelial cells and inhibition of in vivo VEGF signaling to retard liver cyst growth in pkd2(WS25/-) mice indicates the VEGF signaling pathway is a potentially important therapeutic target in the treatment of ADPKD liver cyst disease.