© 2014 World Stroke Organization. Background: Fatigue is a common problem in ischemic stroke survivors. The mechanisms of poststroke fatigue are uncertain yet. The effects of it on functional status have rarely been studied. Aims: The aim of this study was to investigate the risk factors of poststroke fatigue and its effect on activities of daily living and health-related quality of life in Chinese patients with ischemic stroke. Methods: Two hundred and eighteen patients with ischemic stroke formed the study sample. A comprehensive assessment, including the Fatigue Severity Scale, Hamilton Depression Rating Scale, Lawton activities of daily living scale, and the stroke-specific quality of life scale, was conducted three-months after stroke. Magnetic resonance imaging scans focused on the evaluation of infarctions, white matter lesions, and brain atrophy. Results: In the whole sample, with Fatigue Severity Scale as the dependent variable in a linear regression model, Hamilton Depression Rating Scale, prestroke fatigue, and the National Institutes of Health Stroke Scale score at admission were significant correlates of Fatigue Severity Scale, accounting for 36% of the variance of it. When subjects with depression (Hamilton Depression Rating Scale≥20 or current usage of antidepressants) were excluded, only Hamilton Depression Rating Scale and prestroke fatigue remained significant correlates of Fatigue Severity Scale, accounting for 33% of the variance of Fatigue Severity Scale. No magnetic resonance imaging variables correlated with Fatigue Severity Scale. In bivariate correlation analyses, Fatigue Severity Scale was significantly correlated with both activities of daily living and stroke-specific quality of life. In linear regression models, Fatigue Severity Scale independently contributed to activities of daily living accounting for 27% of the variance. Fatigue Severity Scale was also a significant contributor to stroke-specific quality of life accounting for 39% of the variance. Conclusion: Depressive symptoms and prestroke fatigue are major correlates of poststroke fatigue while more severe poststroke fatigue is associated with poorer activities of daily living and health-related quality of life.