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During a 9–year follow–up, 167 consecutive pancreas transplant recipients (152 simultaneous pancreas–kidney [SPK]) were followed for the detection of posttransplant anti–HLA antibodies. Forty patients (24%) developed anti–HLA antibodies, 26 (65%) had donor–specific antibodies (DSA; 61% anticlass 2) and 14 (35%) non–DSA (78.6% anticlass 1). More rejection episodes were observed in patients with positive anti–HLA antibodies than in patients without antibodies (42.5% vs. 11%; p = 0.001), with the highest incidence observed in DSA patients (53.8%). More severe rejections (according to rescue therapy) were observed in DSA patients compared to non–DSA (p < 0.05) or to negative patients (p < 0.001). Contrasting with the kidney, pancreas graft survival did not differ between patients with or without anti–HLA antibodies. On the contrary, pancreas and kidney survivals were significantly lower in DSA positive patients (75% for both organs) as compared to non–DSA positive patients (100% for pancreas and 92% for kidney) or to HLA–negative patients (91% for pancreas and 89% for kidney). Nontechnical pancreas and kidney graft failures were significantly higher in positive than in negative anti–HLA patients (32.5% vs. 11%; p < 0.01). Occurrence of posttransplant DSA was an independent risk factor for both pancreas and kidney survival (HR 3.2; p = 0.039) in diabetic transplant recipients.