Background: A randomized, placebo-controlled clinical trial was undertaken to determine the efficacy of nonpharmacologic individualized interventions (individualized to address unmet needs such as boredom or pain) in decreasing agitation in persons with dementia. Method: Agitated nursing home residents with advanced dementia (from 9 nursing homes in 5 locations in Maryland, United States) were randomized into an intervention group (n = 89) and a placebo control group (n = 36). On the basis of data from baseline assessment, a systematic methodology for individualizing nonpharmacologic interventions, Treatment Routes for Exploring Agitation (TREA), was used with the intervention group: an unmet need was hypothesized, a corresponding treatment category was identified, and specifics of the treatment were chosen to fit the person's need, past identity, preferences, and abilities. (Unmet needs were hypothesized based on physician evaluations, structured staff interviews, relative questionnaires, direct observations of agitation with the Agitation Behavior Mapping Instrument [the primary outcome measure] and affect with Lawton's Modified Behavior Stream [the secondary outcome measure], and resident assessments.) TREA interventions were implemented for 2 weeks, and observations of agitation and affect were recorded. The study was conducted from June 2006 until December 2011. Results: Relative to a control group, TREA interventions for unmet needs produced statistically significant declines in total (P < .001), physical nonaggressive (P < .001), and verbal agitation (P = .004) and significant increases in pleasure (P < .001) and interest (P < .05). Conclusions: This is the first large randomized controlled trial to demonstrate the efficacy of TREA and one of only a few such trials of nonpharmacologic interventions for agitation in persons with dementia. The translation of these findings into practice is sorely needed and would require structural changes dedicating staff time to observing each agitated resident, determining unmet needs, obtaining appropriate intervention materials, conducting the individualized nonpharmacologic interventions, and evaluating results. Trial Registration: ClinicalTrials.gov identifier: NCT00820859.