OBJECTIVES: Cholinesterase (ChE) inhibitors, including donepezil and rivastigmine, are standard of care for mild to moderate cognitive impairment due to Alzheimer's disease (AD). The current study investigates whether treatment with rivastigmine is associated with less use of antipsychotics compared to treatment with donepezil. METHODS: A claims analysis was conducted from 01/2004 through 12/2006 using the MedStat MarketScan database. Patients included had continuous insurance coverage, had at least 1 diagnosis of AD, and were newly initiated on either rivastigmine or donepezil after the first AD claim. Patients using memantine or receiving antipsychotics in the time interval of ≥180 days before and 14 days after the first rivastigmine or donepezil drug dispensing were excluded. Both Kaplan-Meier and multivariate Cox regression analyses were conducted to compare the time to first antipsychotic drug dispensing between the rivastigmine and donepezil groups. RESULTS: A total of 532 patients receiving rivastigmine and 7,264 patients receiving donepezil were studied. The donepezil group was slightly older (81.1 vs. 79.9 years; p=0.0044) with a greater proportion of women (59.4% vs. 53.2%; p=0.0053). The Kaplan-Meier analysis showed that 30 (5.6%) rivastigmine and 589 (8.1%) donepezil patients received antipsychotic medications (Log-rank p=0.0672). Multivariate adjustment showed that rivastigmine was associated with a statistically significant reduction in emergent use of antipsychotic drugs by 34% relative to donepezil (hazard ratio: 0.66; 95% CI: 0.46-0.96; p=0.0305). Among other statistically significant covariates, older age, lower drug dose, baseline depression and neuropsychiatric symptoms, and admission to inpatient long-term care facilities were associated with an increased likelihood of antipsychotic drug use. CONCLUSIONS: Based on real-world data from a large cohort of antipsychotic-naïve patients with AD, rivastigmine was found to be associated with a significant reduction in the emergent use of antipsychotic drugs, compared to donepezil. Prospective studies are needed to verify these findings.