Importance: Substance use disorders are a major source of morbidity and mortality in the United States. National data comparing the prevalence of substance use disorder diagnoses (SUDDs) among transgender and cisgender individuals are lacking in the United States.

Objectives: To investigate the prevalence of SUDDs among transgender and cisgender adults and to identify within-group and between-group differences by age, gender, and geographic location.

Design, Setting, and Participants: This cross-sectional study used the OptumLabs Data Warehouse to analyze deidentified claims from approximately 74 million adults aged 18 years or older enrolled in commercial or Medicare Advantage insurance plans in 2017. A total of 15 637 transgender adults were identified based on a previously developed algorithm using a combination of International Classification of Diseases, Tenth Revision (ICD-10) transgender-related diagnosis and procedure codes and sex-discordant hormone prescriptions. A cohort of 46 911 cisgender adults was matched to the transgender cohort in a 3:1 ratio based on age and geographic location.

Main Outcomes and Measures: SUDDs, based on ICD-10 codes, were assessed overall and compared between transgender and cisgender cohorts and by geographic region (ie, Northeast, Midwest, South, and West); age groups (eg, 18-25, 26-30, 31-35 years), and gender (ie, transfeminine [TF; assigned male sex at birth, identify along feminine gender spectrum], transmasculine [TM; assigned female sex at birth, identify along masculine gender spectrum], male, and female).

Results: In this study of 15 637 transgender adults (4955 [31.7%] TM) and 46 911 cisgender adults (23 664 [50.4%] men), most (8627 transgender adults [55.2%]; 51 762 cisgender adults [55.2%]) were aged between 18 and 40 years, and 6482 transgender adults (41.5%) and 19 446 cisgender adults (41.5%) lived in the South. Comparing transgender to cisgender groups, significant differences were found in the prevalence of a nicotine (2594 [16.6%] vs 2551 [5.4%]; P < .001), alcohol (401 [2.6%] vs 438 [0.9%]; P < .001), and drug (678 [4.3%] vs 549 [1.2%]; P < .001) SUDDs. Among transgender adults, cannabis was the most prevalent drug SUDD (321 [2.1%]), followed by opioid SUDD (205 [1.3%]) and cocaine SUDD (81 [0.5%]), whereas among cisgender adults, cannabis and opioid SUDDs were equally prevalent (cannabis, 186 [0.4%]; opioid, 207 [0.4%]), followed by cocaine SUDD (59 [0.1%]).

Conclusions and Relevance: In this study, the prevalence of SUDDs was significantly elevated among transgender adults relative to their cisgender peers. These findings underscore the need for culturally tailored clinical interventions to treat substance use disorder in transgender populations.