Placebos prescribed as 'regular' medication can reduce symptoms of depression. However, using a placebo without patients' informed consent presents ethical issues. Therefore, the present study assessed the efficacy of an open-label placebo (OLP), which was administered concurrently with cognitive-behavioral therapy (CBT).Sixty patients (mean age: 48 years) diagnosed with major depressive disorder were randomly assigned to a 4-week CBT outpatient program with or without daily OLP treatment. The patients were assessed directly before and after the program as well as three months after the therapy.Compared to the CBT group, the CBT + OLP group showed a greater reduction in symptoms of depression at the end of the program. Changes in categories pertaining to severity of depression did not differ between groups. All patients completed the program. Noncompliance with the follow-up appointment differed significantly between CBT + OLP (27%) and CBT (7%). Noncompliance was associated with a negative evaluation of the OLP.The OLP intervention reduced symptoms of depression, however, these changes were not clinically meaningful. The OLP increased the risk for loss to follow-up. The high dropout rate in the present study raises questions concerning the acceptance of OLPs in the treatment of depression.