OBJECTIVES:  Behavioral and psychological symptoms of dementia (BPSD) in Alzheimer’s disease (AD) greatly increase caregiver burden and often trigger nursing home placement. A systematic review of double-blind randomized controlled trials (RCTs) was conducted to compare the ability of donepezil and memantine to manage BPSD in AD. METHODS:  MEDLINE, EMBASE, Cochrane Library, and hand searches identified 4739 citations, of which 16 studies had Neuropsychiatric Inventory (NPI) data suitable for meta-analysis (6 memantine and ten donepezil trials). All trials were placebo-controlled, and no head-to-head comparisons of the two drugs were identified. A random-effects meta-analysis was conducted using AD severity subgroups to investigate heterogeneity between trials. Thereafter meta-regression was conducted using study level covariates as potential predictors of between-treatment weighted mean difference (WMD) in NPI score. RESULTS: Unadjusted random effects meta-analysis of all 16 RCTs found significant between-study heterogeneity (all studies I2 = 64.4%; donepezil vs. placebo WMD -1.84, 95%CI -3.57, -0.10, I2 = 61%; memantine monotherapy vs. placebo WMD -1.19, 95% CI -3.70, 1.32, I2= 68.7%; memantine + AChEI combination therapy vs. placebo WMD -1.68 95% CI -5.70, 2.33, I2 = 80.4%).  Meta-regression that stratified studies into four AD severity groups measured by Mini-Mental State Exam (MMSE) (severe 0-9, moderately-severe 10-14, moderate 15-20 and mild 21-26) and controlling for age at baseline, found these covariates accounted for most (59.85%) of the between-study variance. Using this meta-regression model, the pooled NPI score for donepezil showed significant improvement compared to placebo (MD -1.50; 95% CI -2.63,-0.36) whereas this was not the case for memantine vs. placebo (MD -1.25; 95% CI -2.63, 0.13).  CONCLUSIONS: Donepezil was associated with significant improvement in the management of BPSD in AD patients compared to placebo, whereas memantine failed to show a significant improvement versus placebo in the management of these symptoms.