If thiazolidinediones have shown beneficial effects on macrovascular endothelial function, their effects on microcirculation and lymphatic function are not well documented. The aim of the study was to assess the effect of rosiglitazone on interstitial albumin retention and lymphatic function in Zucker Diabetic Fatty (ZDF) rats. Three series of 9-14 rats were studied: Lean (fa/?) controls, ZDF (Gmi-fa/fa) rats and ZDF rats treated with rosiglitazone from 8 to 26 weeks of age (ZDF-ROSI). Albumin retention and lymphatic uptake of interstitial albumin (LF/HF ratio) were evaluated on hindquarters with a noninvasive isotopic test using technetium-labelled albumin. Vascular Endothelial Growth Factor (VEGF) was measured. At week 25, albumin retention was markedly higher in ZDF rats (9.9+/-1.0%) than in control rats (1.0+/-0.8%, p<0.001), but did not differ significantly between the ZDF-ROSI group (2.5+/-1.5%) and the control group. LF/HF ratio was similarly increased in the ZDF group (1.14+/-0.07%) and the ZDF-ROSI group (1.07+/-0.04%) as compared to control rats (0.65+/-0.04%; p<0.001 for both). We can deduce that the prevention of the increase of albumin retention under rosiglitazone results from a decrease in the capillary filtration of albumin. VEGF levels were 7.1+/-1.5, 7.3+/-1.9, 3.5+/-1.6 pg/mL in the control, ZDF and ZDF-ROSI groups, respectively (p=0.23). In ZDF rats, rosiglitazone prevents interstitial albumin retention and the increase in capillary filtration of albumin. However lymphatic function is still impaired and might contribute to oedema.