IMPORTANCETransphobia and stigma remain barriers to seeking mental health care for genderdiverse adolescents. OBJECTIVE To examine the utility of brief social contact-based video interventions of transgender protagonists with depression to reduce transphobia and depression-related stigma and increase treatment-seeking intentions among adolescents in the general population. DESIGN, SETTING, AND PARTICIPANTS During August 2021, a total of 1437 participants were recruited and randomly assigned to 1 of 4 video-based conditions in a 2:2:1:1 ratio: (1) transgender adolescent girls, (2) transgender adolescent boys, (3) cisgender adolescent girls, or (4) cisgender adolescent boys. INTERVENTIONS In each of the approximately 110-second videos, an empowered presenter shared their personal story about coping with depression and reaching out for help. MAIN OUTCOMES AND MEASURES The primary outcome was the score on the Attitudes Toward Transgender Men and Women (ATTMW) scale. Secondary outcomes were (1) a "gender thermometer" rating for warmth in transgender perception, (2) the Depression Stigma Scale (DSS) score, and (3) the General Health-Seeking Questionnaire (GHSQ) score. RESULTS Of the 1437 randomized participants, 1098 (76%) completed the postintervention assessment and passed all the validity tests (mean [SD] age, 16.9 [1.2] years; 481 [44%] male; 640 [58%] White). A significant change in attitudes toward transgender youth was found within the intervention group only (mean [SD] ATTMW scores: intervention group, 34.6 [23.1] at baseline to 32.8 [24.2] after intervention; P < .001; control group, 33.5 [23.4] at baseline to 32.4 [24.1] after intervention; P = .01). The mean (SD) total DSS scores decreased significantly across study groups