The aim of this study was to investigate a possible reenhancement of islet cell autoimmunity in type I (insulin-dependent) diabetic patients who received HLA-mismatched pancreas transplants from cadaveric donors and who underwent generalized immunosuppression. Circulating islet cell antibodies (ICA) and complement-fixing ICAs (CF-ICAs) have been tested at 1, 2, 3, 6, and 12 mo and at least once a year posttransplantation in 23 recipients of 25 transplants (22 simultaneous with kidney, 2 retransplants, 1 isolated; 23 segmentai neoprene injected, 2 whole with enteric drainage). Patients were aged 35.3 ± 1.9 yr with a duration of diabetes of 20.6 ±1.1 yr. Immunosuppression consisted of double or triple association of azathioprine, cyclosporin, and prednisone with or without temporary antilymphocyte globulins. The number of HLA-A and HLA-B compatibilities was none in 8 patients, one in 12 patients, two in 4 patients, and three in 1 patient. The mean follow-up was 4.0 ± 0.4 yr/patient (range 0.4–7.2). ICAs were positive pretransplantation in 2 of 25 patients and reappeared 1–42 mo posttransplantation in another 7. In 6 patients, CF-ICAs were also positive. In 7 of 9 ICA+ patients the pancreas transplant failed; in 1 patient this occurred 4 mo before ICA reappearance, and in 6 patients it occurred 2–35 mo after the first detection of ICAs. Pancreas-transplant failure was significantly associated with the positivity for ICAs (P < .05) and particularly for CF-ICAs (P < .005). ICA positivity was transitory in 4 patients (2–27 mo) and persistent in the remaining 5 (up to 61 mo). These findings suggest a possible reenhancement of islet cell autoimmunity in type I diabetic patients after HLA-mismatched pancreas transplantation, which could contribute to some cases of transplant failure.