Background and Purpose-Pancreatic beta-cell dysfunction is an important factor in the development of type 2 diabetes mellitus. This study aimed to estimate the association between beta-cell dysfunction and prognosis of nondiabetic patients with ischemic stroke. Methods-Patients with ischemic stroke without a history of diabetes mellitus in the ACROSS-China (Abnormal Glucose Regulation in Patients with Acute Stroke across China) registry were included. Disposition index was estimated as computer-based model of homeostatic model assessment 2-beta%/homeostatic model assessment 2-insulin resistance based on fasting C-peptide level. Outcomes included stroke recurrence, all-cause death, and dependency (modified Rankin Scale, 3-5) at 12 months after onset. Results-Among 1171 patients, 37.2% were women with a mean age of 62.4 years. At 12 months, 167 (14.8%) patients had recurrent stroke, 110 (9.4%) died, and 184 (16.0%) had a dependency. The first quartile of the disposition index was associated with an increased risk of stroke recurrence (adjusted hazard ratio, 3.57; 95% confidence interval, 2.13-5.99) and dependency (adjusted hazard ratio, 2.30; 95% confidence interval, 1.21-4.38); both the first and second quartiles of the disposition index were associated with an increased risk of death (adjusted hazard ratio, 5.09; 95% confidence interval, 2.51-10.33; adjusted hazard ratio, 2.42; 95% confidence interval, 1.17-5.03) compared with the fourth quartile. Using a multivariable regression model with restricted cubic spline, we observed an L-shaped association between the disposition index and the risk of each end point. Conclusions-In this large-scale registry, beta-cell dysfunction was associated with an increased risk of 12-month poor prognosis in nondiabetic patients with ischemic stroke.