Importance: Gender affirming treatment aims to improve mental health. Objective: To investigate longitudinal mental health outcomes in Danish transgender persons. Design: National register-based cohort study in Danish transgender persons with diagnosis code of “gender identity disorder” during the period 2000-2021. Participants: Five age-matched controls of the same sex at birth and five age-matched controls of the other sex at birth were included for each transgender person. Main outcomes: Diagnosis codes of mental and behavioral disorders and/or prescription of psychopharmacological agents until June 2022. Results: The cohort included 3812 transgender persons with median age (interquartile range) 19 (15; 24) years for persons assigned female at birth (AFAB, N = 1993) and 23 (19; 33) years for persons assigned male at birth (AMAB, N = 1819) and 38 120 controls. Follow up duration was up to 10 years with mean (standard deviation) 4.5 (4.3) years. In transgender persons AFAB compared to control women, the odds ratio (OR) (95% confidence interval) for mental and behavioral disorders was 6.7 (5.5; 8.1) before the index date, 9.9 (8.4; 11.7) at 1 year, 5.8 (4.4; 7.7) at 5 years, and 3.4 (2.1; 7.5) at 8 years follow up. In transgender persons AMAB compared to control men, corresponding ORs were 5.0 (4.0; 6.4), 11.3 (9.3; 13.7), 4.8 (3.5; 6.5), and 6.6 (4.2; 10.3) at 8 years follow up (all P < .001). Conclusion: The OR for mental health disorders was higher in transgender persons compared to controls and remained elevated throughout follow up, especially in transgender persons AMAB.