Purpose: Transgender adolescents are at risk for internalizing and externalizing problems, along with high suicidality rates, and poor peer relations. The present study compared transgender adolescents before and after gender-affirmative care with a sample of nonclinical age-equivalent cisgender adolescents from the general population on psychological well-being and aimed to investigate the possible effect of transgender care involving puberty suppression. Methods: In this cross-sectional study, emotional and behavioral problems were assessed by the Youth Self-Report in a sample of 272 adolescents referred to a specialized gender identity clinic who did not yet receive any affirmative medical treatment and compared with 178 transgender adolescents receiving affirmative care consisting of puberty suppression and compared with 651 Dutch high school cisgender adolescents from the general population. Results: Before medical treatment, clinic-referred adolescents showed more internalizing problems and reported increased self-harm/suicidality and poorer peer relations compared with their age-equivalent peers. Transgender adolescents receiving puberty suppression had fewer emotional and behavioral problems than the group that had just been referred to transgender care and had similar or fewer problems than their same-age cisgender peers on the Youth Self-Report domains. Conclusions: Transgender adolescents show poorer psychological well-being before treatment but show similar or better psychological functioning compared with cisgender peers from the general population after the start of specialized transgender care involving puberty suppression.