Despite improved pancreas transplant graft survival, early diagnosis of rejection remains a clinical challenge. Using a canine model of whole pancreas transplantation with bladder exocrine drainage we have shown fine needle aspiration biopsy (FNAB) to provide an earlier diagnosis of rejection than fall in urinary amylase (UA). The aim of this study was to assess the ability of anti-rejection therapy to reverse rejection when the diagnosis was based on either FNAB findings or a fall of UA. Sixteen dogs received a total pancreas allograft with an inadequate dose of oral cyclosporine (5 mg/kg/day). Fasting UA levels were measured daily and percutaneous FNAB with ultrasound guidance was performed three times weekly on all dogs. The diagnosis of rejection was made in alternate dogs with either a fall of UA to a level of less than 5000 IU/liter (median 7 days) or when the total corrected increment (TCI) of aspirated infiltrating cells was greater than 2.6 (median 5 days). Anti-rejection therapy consisted of methylprednisolone 10 mg/kg/day iv for 5 days and an increase of oral cyclosporine dosage to 25 mg/kg/day. Early vascular thrombosis (Day 2) occurred in three allografts. Diagnosis of rejection based on a low level of UA permitted the successful reversal of rejection in only one of six grafts, whereas five of seven grafts were successfully treated when rejection diagnosis was based on FNAB. Median allograft survivals were 9 days (range 8-19) and 32 days (range 11-63), respectively (P less than 0.01). The earlier diagnosis of allograft rejection made by FNAB improved the ability of conventional anti-rejection therapy to reverse pancreas allograft rejection and significantly improved allograft survival.