Objective: To evaluate the efficacy and safety of memantine in patients with mild to moderate Alzheimers disease (AD) receiving cholinesterase inhibitor (ChEI) treatment. Methods: Participants (N= 433) with probable AD, Mini-Mental State Exam (MMSE) scores between 10-22 (inclusive), and concurrent stable use of ChEIs (donepezil, rivastigmine, galantamine) were randomized to placebo or memantine (20 mg once daily) for 24 weeks. Primary outcomes were changes from baseline on the Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-cog) and on Clinicians Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) score. Secondary measures comprised the 23-item Alzheimer Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL23), Neuropsychiatric Inventory (NPI), and MMSE. Results: At the end of the trial, there were no statistically significant differences between the memantine- and placebo group on primary and secondary outcome measures. The incidence of adverse events (AEs) was similar between the two groups, with no AE occurring in more than 5% of memantine-treated patients and at a rate twice that of the placebo group. Conclusions: In this trial, memantine did not show an advantage over placebo based on protocol- specified primary or secondary analyses in patients with mild to moderate AD on stable ChEI regimens. There were no significant differences in tolerability and safety between the memantine- and placebo groups.