Efficacy and dose-effect relationship of donepezil for treating patients with Alzheimer's disease (AD) have been proven. However, few studies focused on the safety of donepezil, particularly in Chinese patients. To assess the safety of donepezil 10 mg/day in Chinese patients with mild-to-moderate AD. In this single-arm, prospective, multicenter trial, 241 patients with mild to moderate AD who had been treated with donepezil 5 mg/day for at least 4 weeks were enrolled. All patients received donepezil 10 mg/day for 20 weeks. Primary outcome was the incidence of adverse events (AEs). Safety profile was evaluated by physical examinations including vital signs and weight, clinical laboratory tests and electrocardiograms, and also correlation analysis between AEs and APOE genotypes. 241 patients were enrolled. Of which, 38.59% patients experienced at least one AE and 17.43% discontinued due to AEs. Most AEs were mild to moderate, with diarrhea, vomiting, and nausea the most frequently reported. Risk of AEs was significantly increased by concomitant use of drugs for cardiovascular and cerebrovascular diseases. Mean changes in heart rate and corrected QT relative to baseline were -1.08±6.02 beat/min (p = 0.009) and -3.91±18.68 ms (p = 0.0062) at week 4 and -1.48 beat/min±7.18 (p = 0.0028) and -0.66 ms±19.66 (p = 0.6561) at week 20, respectively. There were no significant changes in other vital sign parameters. Patients' MMSE scores improved significantly after treatment (p = 0.0038), especially for non-APOEɛ4 allele carriers and patients ≤75 years. Donepezil 10 mg/day can be tolerated and is effective in Chinese patients with mild-to-moderate AD.