Background: Since current therapies for depression are effective but not for all patients alike, we need to further improve available treatments. Existing research suggests that acceptance and commitment therapy (ACT) may effectively treat major depressive disorder (MDD). We compared ACT with cognitive behavioral therapy (CBT) for depression, testing the hypothesis that CBT would outperform ACT. Methods: We conducted a randomized controlled trial with 82 patients suffering from MDD. Data were collected before and after treatment and at the 6-month follow-up, assessing diagnosis, symptom levels of depression, and quality of life. Results: After treatment, the rates of remission from depression were 75 and 80% for the ACT and CBT conditions, respectively. Patients in both conditions further reported significant and large reductions in depressive symptoms and improvement in quality of life from before to after treatment as well as at the follow-up. Our findings indicated no significant differences between the two intervention groups. Conclusion: Our results indicate that CBT is not more effective in treating depression than ACT. Further research is needed to investigate whether ACT and CBT work differently for different groups of patients with depression.