OBJECTIVE: To determine the impact of islet transplantation (ITx) on hypoglycemia awareness in patients with unstable type 1 diabetes and its relation to islet function. RESEARCH DESIGN AND METHODS: A total of 31 ITx recipients were studied. Hypoglycemia unawareness was assessed using the Clarke hypoglycemic score (0 = no hypoglycemia; >or=4 = hypoglycemia unawareness). Subjects were grouped based on graft function: off-insulin (n = 8), graft dysfunction (on-insulin and stimulated C-peptide >or=0.3 ng/ml, n = 13), and graft failure (stimulated C-peptide <0.3 ng/ml, n = 10, evaluated 11.5 +/- 14.5 months after graft failure). RESULTS: The hypoglycemia score improved after ITx when compared with baseline values (before vs. after: 5.29 +/- 1.51 vs. 1.35 +/- 1.92, P < 0.001). This result was sustained even after patient stratification based on islet function (pre vs. post off-insulin: 5.63 +/- 2.00 vs. no hypoglycemia reported; graft dysfunction: 5.31 +/- 1.49 vs. 1.15 +/- 1.63, P < 0.001; and graft failure: 5.00 +/- 1.16 vs. 2.70 +/- 2.26, P = 0.014). CONCLUSIONS: The improved metabolic control achieved with ITx can restore hypoglycemia awareness in patients with type 1 diabetes, persisting even after islet graft failure.