ABSTRACT: BACKGROUND:Depression is the leading cause of disability in youth, with a global economic burden of US >$210 billion annually. However, up to 70% of youth with depression do not receive services. Even among those who do access treatment, 30% to 65% fail to respond and many dropout prematurely, demonstrating a need for more potent, accessible interventions. In a previous trial, a single-session Web-based growth mindset (GM) intervention significantly reduced depressive symptoms in high-symptom adolescents; however, this intervention did not benefit adolescents uniformly. For instance, the intervention reduced depression in adolescents who reported post intervention increases in perceived control, but it did not lead to significant depression reductions in adolescents who reported no significant post intervention increases in perceived control. OBJECTIVE:The goal of this project is to test the acceptability and efficacy of a novel, single-session, virtual reality (VR) depression intervention-the VR Personality Project-teaching GM, the belief that personal attributes are malleable rather than fixed. The VR Personality Project was designed to systematically target and increase adolescents' perceived control by offering a more immersive, engaging, user-directed intervention experience than the Web-based intervention can provide. By targeting an identified predictor of intervention response, the VR Personality Project may lead to larger reductions in depressive symptoms than existing Web-based mindset interventions. METHODS:Adolescents with elevated depressive symptoms or a recent history of depression (N=159; ages 12 to 16 years) will be randomized to one of 3 intervention conditions: the VR Personality Project; the Web-based GM intervention tested previously; or an active, Web-based control. Adolescents and their parents will report on the adolescents' depression symptoms, perceived control, and related domains of functioning at preintervention, postintervention, and at 3- and 9-month follow-up assessments. RESULTS:We predict that the VR and Web-based mindset interventions will both lead to larger reductions in adolescent symptoms than the control intervention. Additionally, we predict that the VR-based single session intervention will lead to larger reductions in depression than the online mindset intervention and that these symptom reductions will be mediated by increases in adolescents' perceived control from pre- to postintervention. CONCLUSIONS:The results may suggest an efficient strategy for reducing adolescent depressive symptoms: One that is mechanism-targeted, relatively affordable (less than US $200 for a commercially available VR headset, a fraction of the cost of long-term psychotherapy) and potentially engaging to adolescents experiencing mood-related distress. TRIAL REGISTRATION:ClinicalTrials.gov NCT0385881; https://clinicaltrials.gov/ct2/show/NCT03858881 (Archived by WebCite at http://www.webcitation.org/78C3roDgA). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/13368.