Neuropsychological performance was examined in healthy elderly participants administered the cholinesterase inhibitor donepezil. Of principal interest was examination of the sensitivity of a series of neuropsychological measures to detect cognitive changes after drug administration using typical phase I research parameters (eg, a small sample over a short treatment period). In this double-blind parallel study over a period of 6 weeks, 26 healthy elderly participants (aged 55 to 75 years) were randomized into 1 of 2 arms (14 donepezil and 12 placebo) and completed 14 days of donepezil (5 mg, twice a day) or placebo (twice a day). A battery of neuropsychological tests was administered on days 0, 14 (prerandomization), 28 (end of treatment), and 42 (washout). After 2 weeks of donepezil treatment (day 28), subjects in the donepezil group performed slightly but significantly worse on 2 tests of speed, attention, and short-term memory (P < 0.05) compared with the placebo group. No significant improvement in performance was present on any test during treatment with donepezil. These results are consistent with a previous study in healthy young participants in which transient mild worsening on some cognitive tests during donepezil administration was observed, possibly caused by perturbation of an already optimized cholinergic system in healthy participants. These results are important to consider when designing clinical development plans for putative cognitive-enhancing drugs; in addition, these results raise questions about when the optimal point to begin treatment is for patients who have not yet met criteria for dementia.