BACKGROUND: Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be safe and to have beneficial effects on cognition, function, behavior, and global patient status in patients with Alzheimer's disease (AD) in studies lasting 3-6 months. It is approved in the U.S. and Europe for the treatment of moderate to severe AD and is currently under investigation for mild to moderate AD. OBJECTIVE: To evaluate the long-term safety of memantine in patients with mild to moderate AD and to investigate the tolerability of once-daily dose administration. METHODS: This 28-week study enrolled 314 patients with mild to moderate AD who had completed a 24-week, double-blind, placebo-controlled lead-in clinical trial of memantine in AD. Following an 8-week double-blind dose titration phase (used to assess the tolerability of different dosing regimens), subjects were assigned to continuous open label memantine (10 mg, bi.d.) treatment for 20 weeks. Safety outcome measures included treatment-emergent adverse events (AEs), deaths, vital signs, electrocardiograms, and laboratory parameters. RESULTS: During the 28-week study (Phase A+Phase B), the most common AEs were falls and other injuries (both 10.8%). AEs resulted in treatment discontinuation in 6.7% of patients. Discontinuations due to AEs were similar in the once-daily dosing groups compared to the twice-daily dosing groups. During dose titration, completion rates were greater than 90% for both groups. Conversion to once-daily dosing in patients already receiving twice-daily doses of memantine was also well tolerated. CONCLUSIONS: Memantine monotherapy in patients with mild to moderate AD is safe and well tolerated for at least one year. Once-daily dosing during titration and short-term maintenance therapy is safe and well tolerated.