Islet transplantation is an effective therapy for life‐threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet‐specific T‐cells in recipients within an islet transplant program favoring alemtuzumab lymphodepleting induction and examined associations with graft function. 58 recipients were studied: 23 pre‐transplant; 40 post‐transplant (including 5 with pre‐transplant phenotyping). The proportion with islet‐specific T‐cell responses was not significantly different over time (pre‐Tx: 59%; 1‐6m post‐transplant: 38%; 7‐12m: 44%; 13‐24m: 47%; >24m: 45%). However, phenotype shifted significantly, with IFN‐γ‐dominated response pre‐transplant replaced by IL‐10‐dominated response in the 1‐6m post‐transplant group, reverting to predominantly IFN‐γ‐oriented response in the >24m group. Clustering analysis of post‐transplant responses revealed two main agglomerations, characterized by IFN‐γ and IL‐10 phenotype respectively. IL10–oriented post‐transplant response was associated with relatively low graft function. Recipients within the IL‐10+ cluster had a significant decline in C‐peptide levels in the period preceding the IL‐10 response, but stable graft function following the response. In contrast, an IFN‐γ response was associated with subsequently decreased C‐peptide. Islet transplantation favoring alemtuzumab induction is associated with an initial altered islet‐specific T‐cell phenotype but reversion towards pre‐transplant profiles over time. Post‐transplant autoreactive T‐cell phenotype may be a predictor of subsequent graft function.