The latency of P300 “cognitive” event-related potentials changes if cholinergic activities of the central nervous system are pharmacologically manipulated. We tested the hypothesis that the new cholinesterase inhibitors donepezil (DPZ) and rivastigmine (Riv) may have an effect on the frequently abnormal P300 component in patients with Alzheimer disease (AD), thereby allowing a significant evaluation of cholinesterase inhibitors. We evaluated 60 patients with mild to moderately severe probable AD, in comparison with 60 age-matched control subjects, with P300 recordings and neuropsychologic examinations. Forty patients were randomly assigned in a double-blinded trial to 5–10 mg/d DPZ versus 2,000 IU/d vitamin E, and 20 patients were instead treated in an open trial with 1.5 to 12 mg/d Riv. In patients treated with vitamin E, we observed latency increments (7.4 ± 3.5 msec) correlated with worsening neuropsychologic test scores. In patients treated with DPZ and Riv, we found significant P300 latency reductions (15.3 ± 3.2 msec and 22.0 ± 3.3 msec). Shorter P300 latencies were associated with higher Wechsler Adult Intelligence Scale scores and with lower AD Assessment Scale–cognitive subscale (ADAS-cog) scores (R= 0.72). Correlations between ADAS-cog changes and P300 changes significantly separated patients treated with DPZ and Riv from those treated with vitamin E. Administration of DPZ and Riv reduced the latencies of P300 components proportionately to neuropsychologic test improvements. Combined P300 and neuropsychologic test evaluation significantly separated DPZ-treated patients and Riv-treated patients from vitamin E-treated patients.