BackgroundChronic pain, affecting approximately 20% of the global population, is the leading cause of disability worldwide. Transgender individuals are disproportionately exposed to chronic pain risk factors compared with the cisgender population. This study compares the incidence of chronic pain between transgender and cisgender individuals and examines the impact of gender affirming hormone therapy, anxiety, and depression on chronic pain.MethodsThe study analysed medical records data of 56,470 transgender men and 41,882 transgender women in the TrinetX database. Six cohorts were created: transgender women either receiving oestrogen or no intervention, transgender men receiving testosterone or no intervention and cohorts of cisgender males and females. Unmatched age‐adjusted incidence rates were calculated. Then cohorts were matched on 22 chronic pain‐associated covariates and the rate of new chronic pain diagnoses was compared between those receiving hormone therapy and those without.ResultsWe observed significantly higher rates of chronic pain among transgender individuals compared with cisgender counterparts. Transgender men on testosterone therapy and transgender women on oestrogen therapy exhibited an increased likelihood of chronic pain diagnoses compared with those not receiving hormone therapy. Individuals with anxiety and depression were more likely to be diagnosed with chronic pain.ConclusionThis study demonstrates a significant burden of chronic pain in transgender individuals, with an increased risk among those receiving hormone therapy. Our study, the first to assess chronic pain in a large cohort of transgender patients, provides support for a potential association between hormone therapy and risk of chronic pain diagnosis. Further research is required to understand causal mechanisms and to develop improved screening and management of chronic pain in transgender populations.Significance StatementOur study, featuring the largest cohort of Transgender and Gender Diverse (TGD) individuals assembled to date, reveals critical disparities in chronic pain among TGD populations, notably those on hormone therapy, compared with the cisgender population. It highlights the urgent need for specialized screening and treatment for this vulnerable population, and research into hormone therapy's impact on pain. These insights aim to foster more effective, personalized healthcare, enhancing the well‐being and quality of life for the TGD community.