ImportanceTransgender youth are at an elevated risk for adverse mental health outcomes compared with their cisgender peers. Identifying opportunities for intervention is a priority.ObjectiveTo estimate differences in the association between gender identity milestones and mental health outcomes among transgender youth, stratified by level of family support.Design, Settings, and ParticipantsThis retrospective cohort study compares changes in mental health outcomes among transgender youth who initiate gender identity milestones compared with those who initiate the same milestones 1 year later, stratified by level of family support, using the 2015 US Transgender Survey. The analytic samples included 18 303 transgender adults aged 18 and older who had initiated at least 1 gender identity milestone between ages 4 and 18 years.ExposureFour gender identity milestones: feeling one’s gender was different, thinking of oneself as transgender, telling another that one is transgender, and living full-time in one’s gender identity, stratified by 3 levels of family support: supportive, neutral, and adverse.Main OutcomesAge at first suicide attempt and at running away.ResultsStudy participants included 18 303 transgender adults (10 288 [56.2%] assigned female at birth; 14 777 [80.7%] White). Initiating a gender identity milestone was associated with a higher risk of suicide attempt and running away from home among transgender youth. This finding was driven by children who live in unsupportive families. For example, thinking of oneself as transgender was associated with a meaningful increase in the overall probability of attempting suicide among those in either adverse families (estimate = 1.75 percentage points; 95% CI, 0.47-3.03) or neutral families (estimate = 1.39 percentage points; 95% CI, 0.72-2.05). Among youth living with supportive families, there were no statistically significant associations between gender identity milestones and adverse mental health outcomes and 95% CIs generally ruled out any meaningful associations.ConclusionThese results demonstrate that without a supportive family environment, gender identity development increases the risk of transgender youth attempting suicide or running away from home. Social services and community resources to establish supportive relationships between transgender children and their parents are essential.