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Background Gender minority individuals, on average, experience higher rates of mental health problems. Mounting work suggests that gender minority stress (GMS) contributes to mental health outcomes in transgender/gender-nonconforming individuals. Aim We assessed whether GMS decreased in transgender people after initiating gender-affirming hormone therapy (GAHT), and we identified social predictors and hormonal associations for GMS at 2 time points. Methods GMS was surveyed through self-report questionnaires tapping into proximal and distal stressors and coping constructs following the minority stress framework. Eighty-five transgender persons wishing to undertake hormonal interventions were assessed prospectively at start of GAHT and after 7.7 ± 3.5 months (mean ± SD). Sixty-five cisgender persons served as a control group. Outcomes (1) Proximal stressors were surveyed by the Beck Depression Inventory II, State-Trait Anxiety Inventory, Scale for Suicide Ideation, Suicidal Thoughts/Attempts, Stigma Consciousness Questionnaire, and Perceived Stress Scale; (2) distal stressors by the Everyday Discrimination Scale; and (3) coping constructs by the Resilience Scale, social network, social standing, and Marlowe Crowne Social Desirability Scale. Results Transgender people experienced higher rates of proximal stressors (Beck Depression Inventory II, State-Trait Anxiety Inventory, Scale for Suicide Ideation, Suicidal Thoughts/Attempts, Perceived Stress Scale) and had lower protective factors (social standing) prior to and during GAHT than cisgender people. Social network and resilience were lower in transgender people relative to cisgender peers only at baseline. Prospectively, decreasing trait anxiety was observed in transgender people. Social factors were adequate predictors of multiple GMS constructs. Specifically, a major role for social network emerged. As for hormonal associations, only serum estradiol levels in transgender women with GAHT were negatively associated with trait anxiety and suicidal thoughts/attempts but positively with resilience and social desirability. Clinical Implications Stimulating a social environment supportive of diverse identities, particularly by investing in social networks as a resource for resilience, is likely to alleviate GMS. Strengths and Limitations Longer duration of interventions with sex steroid treatment, with continued resilience-enhancing strategies, is needed to observe further alleviation of GMS in transgender persons. Also, objective and subjective GMS identification with heteronormative attitudes and beliefs should be surveyed for good measure when assessing GMS. Conclusion Transgender people experienced more GMS throughout study visits than cisgender people did. With a relatively short period of GAHT, some significant changes in and predictors for experienced GMS emerged.