Polycystic kidney disease (PKD) is the commonest inherited cause of kidney failure and it is characterised by relentless growth of fluid-filled renal cysts. To-date, most treatment strategies have targeted cellular dysfunction of cystic epithelia but this approach has yet to generate clinically robust therapies for PKD. We took an alternative approach and hypothesised that the vasculature around cysts was aberrant and, if so, that it would be a novel therapeutic target. We characterised the kidney microvasculature in two mouse models of PKD, namely homozygous hypomorphic Pkd1nl and null mutant Cys1cpk mice using probes for CD31, a pan-endothelial marker, and vascular endothelial growth factor receptor 3 (VEGFR3), a presumed lymphatic marker. Mice were put under terminal anaesthesia by inhalation of isoflurane (4% in oxygen) and blood samples collected from the heart. Kidneys were then perfusion fixed for immunohistochemistry. In wild-type mice, microvasculature surrounding tubules was visualised as a fine linear network. In PKD, the percentage area of CD31+ and VEGFR3+ vessels in the kidney was significantly increased compared with wild-type littermates, due to disorganisation and dilation of the peri-cystic vasculature. To target aberrant microvasculature, Pkd1nl and Cys1cpk mice were administered recombinant VEGFC, which acts through VEGF receptors VEGFR3 and VEGFR2, impacting on morphogenesis and turnover of blood and lymphatic endothelia. VEGFC significantly reduced average cyst size and body/kidney weight ratio compared with untreated mice (see Figure). In the Pkd1nl mice blood urea nitrogen, a measure of renal function, was significantly improved (± S.E.M. 22.9 mg/dL ± 4.15 and 37.10 mg/dL ± 5.29 in treated and untreated mice respectively, p < 0.05 by Mann Whitney U test). The effect was not due to direct actions on cyst epithelia, which were negative for the VEGF receptors. Instead, VEGFC significantly enhanced proliferation of CD31+ and VEGFR3+ blood vessels which restored the normal vascular patterning associated with a decrease in the percentage area of CD31+ and VEGFR3+ vessels. VEGFC also decreased the number of CD206+ macrophages, cells known to be cystogenic. Thus, VEGFC improves PKD and this novel observation points to new therapeutic avenues, with the potential to complement current approaches directly targeting PKD epithelia.