Background: Agitation is a common, challenging symptom affecting large numbers of people with dementia and impacting on quality of life (QoL). There is an urgent need for evidence-based, cost-effective psychosocial interventions to improve these outcomes, particularly in the absence of safe, effective pharmacological therapies. This study aimed evaluate the efficacy of a person-centered care and psychosocial intervention (WHELD) on QoL, agitation and antipsychotic use in people with dementia living in nursing homes, and to determine its cost. Methods and Findings: This was a randomized controlled cluster trial conducted between 1st January 2013 and 30th September 2015 which compared the WHELD intervention with treatment as usual in people with dementia living in 69 UK nursing homes, using an intention to treat analysis. All nursing homes allocated to the intervention received staff training in person-centered care (PCC), social interaction (SoI) and education regarding antipsychotic medications (AM) followed by ongoing delivery through a care staff champion model. Primary outcome measure was QoL (DEMQOL-proxy). Secondary outcomes were agitation (Cohen Mansfield Agitation Inventory), neuropsychiatric symptoms (NPI), antipsychotic use, global deterioration (CDR), mood (Cornell Scale for Depression in Dementia CSSD), unmet needs (Camberwell Assessment of Need in the Elderly CANE), mortality, quality of interactions (Quality of Interactions Scale –QUIS), pain (Abbey) and cost. Costs were calculated using cost function figures compared with usual costs. 847 people were randomized to WHELD or treatment as usual, of whom 553 completed the nine-month RCT. The intervention conferred a statistically significant improvement in QoL (DEMQOL proxy z score 2.82, p=0.0042, Mean Difference 2.54 SEM 0.88, 95% Confidence Intervals (CI) 0.81, 4.28, Cohen’s D Effect Size 0.24). There were also statistically significant benefits in agitation (CMAI Z score 2.68 p=0.0076, Mean Difference 4.27 SEM 1.59, 95% CI -7.39, -1.15, Cohen’s D 0.23) and overall neuropsychiatric symptoms (Z score 3.52 Mean Difference 4.55 SEM 1.28 p=0.00045, 95% CI -7.07,-2.02, Effect Size 0.30). Benefits were greatest in people with moderate-moderately severe dementia. There was a statistically significant benefit in positive care interactions as measured by QUIS (19.7% increase, SEM 8.94, 95% CI 2.12, 37.16, Cohen’s D 0.55, P=0.03). There were no statistically significant differences between WHELD and treatment as usual for the other outcomes. A sensitivity analysis using a pre-specified imputation model confirmed statistically significant benefits in DEMQOL proxy, CMAI and NPI with the WHELD intervention. Antipsychotic drug prescribing was at a low stable level in both treatment groups and the intervention did not reduce use. The WHELD intervention reduced cost compared to treatment as usual, and the benefits achieved were therefore associated with a cost saving. The main limitation was that antipsychotic review was based on augmenting processes within care homes to trigger medical review and did not in this study involve proactive primary care education. An additional limitation was the inherent challenge of assessing QoL in this patient group. Conclusions: These findings suggest that the WHELD intervention confers benefits to QoL, agitation and neuropsychiatric symptoms, albeit with relatively small effect sizes, as well as cost saving in a model that can readily be implemented into nursing homes. Future work should consider how to facilitate sustainability of the intervention in these settings. Trial registration: ISRCTN Registry ISRCTN62237498