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Background and Purpose: Pancreatic β-cell dysfunction is an important factor in the development of type 2 diabetes. This study aimed to estimate the association between β-cell dysfunction and prognosis of nondiabetic patients with ischemic stroke.Methods: Patients with ischemic stroke without a history of diabetes in the Abnormal Glucose Regulation in Patients with Acute Stroke across China (ACROSS-China) registry were included. Disposition index (DI) was estimated as computer-based model of homeostatic model assessment (HOMA2)-β%/ HOMA2-IR based on fasting C-peptide level. Outcomes included stroke recurrence, all-cause death and poor outcome (modified Rankin Scale 3-6) at 12 months after onset.Results: Among 1171 patients, 37.2% were female with a mean age of 62.4 years. At 12 months, 167(14.8%) patients had recurrent stroke, 110(9.4%) died, and 294(25.6%) had a poor outcome. The first quartile of the DI was associated with an increased risk of stroke recurrence (adjusted hazard ratio [HR] 3.57, 95% confidence interval [CI] 2.13-5.99); both the first and second quartiles of the DI were associated with an increased risk of death (adjusted HR 5.09, 95% CI 2.51-10.33; adjusted HR 2.42, 95% CI 1.17-5.03) and poor outcome (adjusted odds ratio [OR] 3.83, 95% CI 2.27-6.48; adjusted OR 2.06, 95% CI 1.25-3.42) compared with the fourth quartile. Using a multivariable regression model with restricted cubic spline, we observed an L-shaped association between the DI and the risk of each endpoint.Conclusions: In this large-scale registry, β-cell dysfunction was associated with an increased risk of 12-month poor prognosis in nondiabetic patients with ischemic stroke.