["Journal of Traumatic Stress, EarlyView. ", "\nABSTRACT\nTransgender and gender expansive (TGE) people experience high levels of posttraumatic stress disorder (PTSD). Gender‐affirming medical interventions (GAMIs) may be helpful in reducing PTSD symptoms. This study examined whether GAMIs were associated with reduced PTSD symptom severity longitudinally and whether the association was mediated by gender minority stress (GMS) and depressive symptoms. TGE participants (N = 2,514) from a national cohort study were included if they attained at least one GAMI at one or more points during 2019–2022. Two longitudinal models were run, adjusted for time and baseline covariates: (a) an interrupted time series analysis (ITSA) examining changes in PTSD scores after receiving at least one GAMI (GAMI indicator) at each annual time point and (b) a mixed‐effects longitudinal model examining the association between GAMI count and PTSD scores. Structural equation modeling tested whether latent GMS and depressive symptoms mediated these longitudinal associations. Unadjusted and minimally adjusted models demonstrated significant PTSD score reductions (a) immediately after the third GAMI indicator (ITSA model), Bunadjusted = ‐0.70, p = .017; Bmin. adjusted = ‐0.61, p = .037, and (b) as GAMIs accumulated, mixed‐effects: Bunadjusted = ‐0.09, p = .001; Bmin. adjusted = ‐0.06, p = .033, with support for depression and GMS mediating these effects. These findings suggest that cumulative GAMIs may be linked to meaningful reductions in PTSD symptoms among TGE individuals. This effect appears to be influenced by improvements in GMS and depression. The results highlight the potential benefits of GAMIs in reducing PTSD burden in TGE populations.\n"]