Purpose: We examined the impact of caregiver neuroticism on longitudinal change in depression among spouse-caregivers of individuals with Alzheimer's disease receiving either enhanced psychosocial treatment or usual care. We were interested in whether high levels of caregiver neuroticism would lead to a diminished response to the enhanced treatment and whether neuroticism affected the longitudinal course of caregiver depression regardless of intervention. Design and Methods: We analyzed data from the NYU Spouse-Caregiver Intervention Study, which randomly assigned caregivers either to an enhanced treatment group that received a comprehensive intervention with counseling, support, and consultation, or to a usual-care control group. The present study analyzed data from 320 caregivers, 160 in each group, who completed the NEO questionnaire. We used random-effects growth curve modeling to examine changes in depression in the first year after intake, examining possible effects of neuroticism on the course of caregiver depression and on response to intervention. Results: Caregivers high in neuroticism showed a worse longitudinal course of depression compared with those low in neuroticism in both the enhanced treatment and usual-care groups after we adjusted for baseline depression as a covariate. Caregivers showed benefits from the enhanced treatment compared with usual care, regardless of neuroticism score. However, caregivers low in neuroticism responded to treatment with declining levels of depression, whereas caregivers high in neuroticism maintained their baseline level of depression. Implications: Caregiver neuroticism is a risk factor for increased caregiver depression over time. High neuroticism does not preclude successful caregiver intervention with a highly individualized intervention like ours, but expectations of outcome should be different than for caregivers low in neuroticism. Future studies should investigate the relationship between neuroticism and response to less individualized interventions and the impact of other personality characteristics on response to treatment.