Cholinesterase inhibitors have been the most frequently used experimental treatment for Alzheimer disease. The early clinical trials of the cholinesterase inhibitor tacrine were primarily small, short-term crossover studies. With the exception of one study reporting dramatic results, most early studies concluded that tacrine had modest therapeutic effects. Because of the variety of study designs and outcomes measures, these results were unreliable indicators of overall efficacy. Tacrine's efficacy has recently been confirmed in several large-scale trials, in which data from more than 1,000 patients were analyzed. Tacrine patients showed statistically significant differences on several cognitive assessments (primarily the Alzheimer's Disease Assessment Scale cognitive subscale), as well as significant differences on functional measures and in clinician and family ratings in some studies. Modest but clinically significant beneficial effects were seen in approximately 26–55% of tacrine-treated patients in these trials.