Sensitivity to psychotropic medications presents a therapeutic challenge when treating neuropsychiatric symptoms in patients with dementia with Lewy bodies (DLB). We compared under randomized, double-blinded conditions the tolerability and efficacy of citalopram and risperidone in the treatment of behavioral and psychotic symptoms in patients with DLB and Alzheimer disease (AD). Thirty-one participants with DLB and 66 with AD hospitalized for behavioral disturbance were treated under randomized, double-blind conditions with citalopram or risperidone for up to 12 weeks. Neuropsychiatric symptoms were assessed with the nursing home version of the Neuropsychiatric Inventory (NPI) and the Clinical Global Impression of Change (CGIC). Side effects were measured using the UKU Side Effect Rating Scale. A significantly higher proportion of participants with DLB (68%) than with AD (50%) discontinued the study prematurely. Discontinuation rates were comparable in DLB participants treated with citalopram (71%) or risperidone (65%). However, participants with DLB randomized to risperidone experienced a higher overall burden of side effects. Scores on the NPI and the CGIC worsened in DLB participants and improved in those with AD. Most patients with behavioral disturbances or psychosis associated with DLB tolerate citalopram or risperidone poorly and do not seem to benefit from either medication.