Although the microvascular endothelium has been identified as the primary target site for the initiation of pancreatic islet graft rejection, little is known of the microvascular and cellular mechanisms involved, partly due to the lack of adequate models. Herein, we present a model for the in vivo assessment of the microcirculation of pancreatic islet grafts in mice. Isolated islets of Langerhans from immunocompetent hairless mice and immunoincompetent athymic nude mice were transplanted syngeneically into a specially designed dorsal skinfold chamber mounted on nondiabetic recipients. The islets' microcirculation was visualized by means of intravital fluorescence microscopy, and microcirculatory parameters were quantitatively analysed over a period of 14 days in the awake animal. Between day 2 and 4 after transplantation 84% (31/37; hairless mice) and 69% (36/52; nude mice) of the islet grafts revealed capillary sprouts and formation of new microvessels. On day 6, these sprouts were found interconnected, and red blood cell movement within the newly formed microvascular network was observed. The process of angiogenesis and revascularization was completed within 10 days after transplantation yielding a glomerulus-like network of capillaries as known for pancreatic islets in situ. Functional capillary density of the islet grafts ranged between 650 and 700 cm-1 in both hairless and nude mice. Within the islets' microvessels neither accumulation of leukocytes nor leukocyte-endothelial cell interaction was observed, indicating the lack of rejection and inflammation in these syngeneic islet grafts. We propose that this model provides a wide spectrum of promising experimental approaches for the study of microcirculatory and cellular mechanisms in free pancreatic islet transplantation.