BACKGROUND: Acceptance and Commitment Therapy for depression (ACT-D) is a promising depression treatment which has not been evaluated on a large scale within VA. This study aimed to evaluate ACT-D's effectiveness in a national, treatment-seeking sample of Veterans. METHODS: The sample comprised 831 Veterans who received a primary depression diagnosis and received at least two sessions of ACT-D during fiscal years 2015-2020. We used GLM to measure predictors of symptom change, treatment response (50 % reduction in PHQ-9 and AAQ-II scores), subthreshold depression symptoms (PHQ-9 < 10; AAQ-II < 27), and treatment completion. RESULTS: Veterans experienced an average reduction of 3.39 points on the PHQ-9 (Cohen's d = 0.56) and 3.76 points on the AAQ-II (Cohen's d = 0.43). On the PHQ-9, 40 % achieved subthreshold depression symptoms. On the AAQ-II, 36 % of Veterans achieved subthreshold psychological inflexibility scores. Service-connected disability rating for depression and higher levels of medical comorbidity were both related to lower levels of overall depression symptom change and treatment response. Substance use disorder and bipolar/psychosis diagnoses were associated with greater reductions in psychological inflexibility. LIMITATIONS: This is an observational study without a control group, so we were unable to compare the effectiveness of ACT-D to other usual care for depression. We were also unable to assess variables that can influence treatment success, such as therapist fidelity and patient engagement. CONCLUSIONS: ACT-D achieved similar improvements in depression as reported in controlled trials. Adaptations to ACT-D may be needed to improve outcomes for Veterans with depression and comorbid PTSD.