Abstract: Multiple studies have shown that the psychological and physical consequences of providing care to a family member with a chronic illness can include anxiety, depressive symptoms, burden, altered immune function, poor overall health, and increased overall mortality. Family caregivers of persons with a primary malignant brain tumor (PMBT) are at particular risk for poor outcomes as they face both oncologic and neurodegenerative issues. Multiple caregiver interventions aimed at improving caregivers’ psychological health have been evaluated, yet meta-analyses fail to demonstrate consistently strong effect sizes. As a result of research suggesting that depressive symptoms interfere with a person’s ability to engage in and benefit from intervention, we hypothesize that current caregiver interventions have not demonstrated large effect sizes because they have not addressed pre-existing levels of depressive symptoms. The long term goals of the project are to identify the most effective ways to deliver interventions to improve the psychological and physical health of family caregivers. The specific aims of this multi-site three arm randomized controlled trial are to: (1) Compare the efficacy of a) an intervention for depressive symptoms (Beating the Blues) delivered prior to a needs-based caregiver intervention (SmartCare©) versus b) SmartCare© alone versus c) enhanced care as usual (CAU+) in improving caregivers’ psychological and physical health and (2) Compare the efficacy of Beating the Blues versus CAU+ in improving subjects’ short-term psychological and physical health. We also plan to explore (1) whether any changes in psychological and physical health resulting from receiving Beating the Blues prior to SmartCare© or SmartCare© alone are maintained at 10-months after baseline and (2) whether the effect of Beating the Blues + SmartCare© (vs. SmartCare© alone) on 4- and 6-month psychological and physical responses is mediated by 0- to 2-month changes in depressive symptoms. We will be recruiting 210 caregiver/care recipient dyads from the University of Pittsburgh Cancer Institute and MD Anderson Cancer Center neuro-oncology clinics. Repeated measures modeling using general linear mixed models will investigate the relationship of group assignment with psychological and physical outcomes over time. The proposed study addresses research priorities set by both NCI and NINR to improve the quality of life of patients and their families and NINR’s emphasis on integrating bio-behavioral science and adopting, adapting and generating new technologies. The significance of the project is great in terms of its potential societal and economic impact. The web-based and telephone intervention delivery allows for easy translation and should the hypotheses be supported, this trial could fundamentally change how caregiver interventions are delivered.