ImportanceWhile acne is common in transgender and gender-diverse people and is associated with gender-affirming hormone therapy, little research has examined these factors and their impact in gender minority groups.ObjectiveTo examine the lived experiences of acne and acne treatment in transgender and gender-diverse participants.Design, Setting, and ParticipantsThis mixed-methods analysis was conducted at a multidisciplinary gender center at a public safety-net hospital and endocrinology and dermatology clinics at a tertiary academic center from January 4, 2021, to April 7, 2022, using semistructured interviews and surveys. Participants were transgender or gender-diverse adults who had received gender-affirming hormone therapy. Data analysis was performed from November 11, 2021, to March 31, 2023.ExposureCurrent diagnosis of acne.Main Outcomes and MeasuresInterviews exploring the experience of acne and acne treatment were audio recorded, transcribed verbatim, coded using minority stress theory and the socioecological model, and analyzed using thematic analysis. Themes were triangulated with survey data on gender, self-reported acne severity, skin-specific quality-of-life impact, and treatment experience.ResultsA total of 32 participants were included in the study (mean [range] age, 32 [18-57] years; 17 transgender men, 11 transgender women, and 4 nonbinary participants). Ten participants (31%) self-rated their skin as currently clear or almost clear, 11 (34%) reported mild acne, and 11 (34%) had moderate to severe acne. Participants described experiences of rejection and bullying related to acne and admitted avoiding social interactions in which they anticipated acne-related discrimination, which led to feelings of depression and anxiety. Acne worsened body appearance dissatisfaction. Transgender women reported acne interfering with feminine gender expression. Transgender men often normalized acne development, sometimes viewing acne positively as an early sign of testosterone action. Most participants tried over-the-counter acne treatments and commonly sought acne treatment advice from physicians, peers, online forums, and social media. Barriers to acne treatments included cost, lack of multidisciplinary care, mistrust toward the health care system, and lack of transgender-specific acne care education.Conclusions and RelevanceIn this mixed-methods study, transgender and gender-diverse individuals reported experiencing acne-related stigma and facing barriers to acne treatment. Multilevel changes, such as developing strategies to reduce acne stigma, providing transgender-specific acne care education, facilitating multidisciplinary acne care, and expanding transgender-friendly clinical environments, are recommended to reduce the impact of acne in transgender individuals.