Transplantation of insulin secreting tissue as a free graft has the potential to become a safe and simple procedure to cure diabetes. However, clinical results, i.e. achievement of insulin independency, are poor, in spite of the use of immunosuppressive regimens, which are regularly successful in whole organ transplantation. In contrast to whole organ grafts, which are revascularized immediately after transplantation, free pancreatic islet grafts require the process of revascularization in order to establish a microvascular network, sufficient for the nutritional blood supply. We have demonstrated for the first time in vivo images of the process of revascularization of free islet xenografts including microvascular phenomena during graft rejection. Rat islet xenografts were isolated by collagenase digestion and transplanted into hamster dorsal skinfold chambers. After 6, 10 and 14 days the microvasculature of the islet grafts was analyzed by means of intravital fluorescence microscopy. Xenogeneic grafts were revascularized during the first 6 days similarly compared to syngeneic grafts; however, on day 10 after transplantation a reduction in size of the microvascular network as well as a decrease in functional capillary density and a reduction in capillary red blood cell velocity were observed, accompanied by microvascular rejection phenomena, such as an increase of microvascular permeability, edema formation, capillary widening and intravascular accumulation of white blood cells (WBCs) with concomitant WBC-endothelium interaction in post-capillary venules. Treatment with 2.5 mg/kg/d (+/-)-15-deoxyspergualin could not completely alleviate these microvascular rejection phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)