Forty-seven patients with probable Alzheimer disease (AD) completed a 6-month double-blind study to compare metrifonate with placebo. The Alzheimer Disease Assessment Scale cognitive subscale score of the metrifonate group treated to a 50-70% inhibition of red blood cell acetylcholinesterase activity differed significantly from the placebo group score by 1.8 points (p < 0.03) due to a deterioration in cognitive performance in the placebo group (p < 0.01). Statistically significant deterioration also occurred in the Mini-Mental State Examination scores (p < 0.01) in the placebo-treated group. Adverse effects were uncommon and did not require adjustment of the dose of metrifonate or discontinuation of treatment. These findings extend our previous report of a favorable effect of metrifonate on cognitive symptoms in AD by showing clinical, not only statistical, significance.