Reliable and timely rejection diagnosis still represents a major problem of pancreas allotransplantation. The aim of this study was to confirm the clinical findings of exocrine function impairment and pancreatic juice cytology during rejection, to refine the latter by means of flow cytometry, and to correlate these changes with graft histology. Heterotopic pancreatic transplants were performed in a modified technique in Lewis rats rendered diabetic by means of streptozotocin from LEW donors (group I, n = 10), Brown Norway rats without immunosuppression (group II, n = 16), and from BN rats where recipients were given cyclosporine 12 mg/kg/BW (group III, n = 10). Pancreatic juice was obtained by daily aspiration from a self-made fully implantable catheter reservoir system. In group II animals acute rejection diagnosed on histomorphological grounds was clearly associated with a decrease in the amount of exocrine secretion and its enzyme content from day 8 on. In contrast to groups I and III, a significant increase in lymphocytes in the pancreatic juice up to 13.5% occurred in group II between days 5 and 7. Activated lymphocytes increased from 7% to 13%, pan-T cells from 193 to 340 events. Histology revealed three distinct phases of acute rejection--phase I: diffuse infiltration of acinar structures; phase II: destruction of interlobular ducts; phase III: vasculitis associated with islet cell damage. The anatomy of the pancreas with the slackness of its highly vascularized interstitial connective tissue facilitates early infiltration of inflammatory cells and migration of these cells into the lumen of the pancreatic duct. Thus pancreatic juice cytology together with an impaired exocrine graft function is highly indicative of acute rejection.