Meta-analyses show that Acceptance and Commitment Therapy (ACT) is an efficacious treatment for a wide range of mental health problems. However, few studies have examined the effectiveness of ACT in naturalistic inpatient settings and in direct comparison to Cognitive Behavior Therapy (CBT). The aim of this study was to investigate the effectiveness of ACT and CBT with regard to depression, general symptom strain and life satisfaction. Method: 177 inpatients in a psychiatric ward were included in the study and assigned to either ACT or CBT group intervention. All patients were assessed with the SCID-I interview and disorder-specific questionnaires as well as with a satisfaction with life scale. To control for confounding variables, amongst others, treatment integrity was evaluated. Results: Both the ACT and CBT intervention showed a large, statistically significant and stable symptom reduction over six months across all outcomes. Both approaches led to small improvement in life satisfaction. With regards to depressive symptoms, more than half of the patients reliably recovered due to therapy. Conclusion: ACT and CBT were similarly effective in treating patients with depressive and other mental disorders in a routine clinical setting. ACT is a viable alternative to CBT for treating inpatients.