OBJECTIVEWe investigated whether changes in islet autoantibody profile and presence of HLA risk markers, reported to predict rapid β-cell loss in pre–type 1 diabetes, associate with poor functional outcome in islet allograft recipients.RESEARCH DESIGN AND METHODSForty-one patients received ≥2.3 million β-cells/kg body wt in one to two intraportal implantations. Outcome after 6–18 months was assessed by C-peptide (random and stimulated), insulin dose, and HbA1c.RESULTSPatients carrying HLA-A*24-positive or experiencing a significant autoantibody surge within 6 months after the first transplantation (n = 19) had lower C-peptide levels (P ≤ 0.003) and higher insulin needs (P < 0.001) despite higher HbA1c levels (P ≤ 0.018). They became less often insulin independent (16% vs. 68%, P = 0.002) and remained less often C-peptide positive (47% vs. 100%, P < 0.001) than recipients lacking both risk factors. HLA-A*24 positivity or an autoantibody surge predicted insulin dependence (P = 0.007).CONCLUSIONSHLA-A*24 and early autoantibody surge after islet implantation associate with poor functional graft outcome.