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-¿-dominated response pre-transplant replaced by IL-10-dominated response in the 1-6m post-transplant group, reverting to predominantly IFN-¿-oriented response in the >24m group. Clustering analysis of post-transplant responses revealed two main agglomerations, characterized by IFN-¿ 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-¿ 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.