OBJECTIVE: This retrospective study was designed to identify metabolic and immune predictors of early islet allograft failure. RESEARCH DESIGN AND METHODS: We measured several metabolic and immunological markers at the time of pretransplant and several time points posttransplantation in 17 patients with long-term functioning graft (long fx) and 20 patients with short-term functioning graft (short fx). RESULTS: The short fx group showed higher insulin resistance, altered proinsulin processing, lower soluble interleukin-2 receptor (sIL-2r) (marker of T-cell activation), and higher soluble FasL (marker of apoptosis) during the entire follow-up, particularly at time of failure. CONCLUSIONS: Patients who experienced an early failure of islet allograft showed specific metabolic and immunological signs long before islet failure.