OBJECTIVE:: To assess the risk of glucose-6-phosphate dehydrogenase (G6PD) on stroke prognosis, we compared outcomes between stroke patients with and without G6PD deficiency. METHODS:: The study recruited 1251 patients with acute ischemic stroke. Patients were individually categorized into G6PD-deficiency and non-G6PD-deficiency groups according to G6PD activity upon admission. The primary endpoint was poor outcome at 3 months defined by a modified Rankin Scale (mRS) score ≥ 2 (including disability and death). Secondary outcomes included the overall mRS scores at 3 months, and in-hospital death and all death within 3 months. Logistic regression and Cox models, adjusted for potential confounders, were fitted to estimate the association of G6PD deficiency with the outcomes. RESULTS:: Among 1251 patients, 150 (12.0 %) were G6PD deficient. Patients with G6PD deficiency had higher proportions of large-artery atherosclerosis (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.09-2.17) and stroke history (OR 1.93, 95% CI 1.26-2.90) compared to the non-G6PD-deficient group. The two groups differed significantly in the overall mRS-score distribution (adjusted common OR 1.57, 95% CI 1.14-2.17). Patients with G6PD deficiency had higher rates of poor outcome at 3 months (adjusted OR 1.73, 95% CI 1.08-2.76; adjusted absolute risk increase 13.0%, 95% CI 2.4%-23.6%). The hazard ratio of in-hospital death for patients with G6PD-deficiency was 1.46 (95% CI 1.37-1.84). CONCLUSIONS:: G6PD deficiency is associated with the risk of poor outcome at 3 months after ischemic stroke and may increase the risk of in-hospital death. These findings suggest the rationality of G6PD screening in patients with stroke.