BACKGROUND: The response to placebo is robust in studies of various antidepressant treatments. The strong placebo response, combined with the absence of side-effects, has prompted suggestions to use the ethically sound open-label placebo (OLP) as a treatment for depression. The aim of the present study was to assess the efficacy of OLP as an adjunct to treatment as usual (TAU) in the setting of a randomized controlled trial for the treatment of unipolar depression. METHODS: Thirty-eight patients (age: 50 ± 17.1; 73.7% females) were randomized to either eight-week OLP treatment (n = 18) or four weeks of TAU followed by four weeks of OLP (n = 20). Clinical and socio-demographic measures were assessed at baseline, after four weeks, and at the end of the trial. Response to treatment was determined using the QIDS SR-16. RESULTS: There was an overall decrease in depression levels over time, F(2,35) = 3.98, p = .028. A significant group x time interaction was found only among non-geriatric patients (<65years) with an early onset of depression (<50years), F(2,22) = 3.89, p = .036. Post-hoc tests indicated a significant decrease during the first four weeks, but only in the OLP group, t(11) = 2.29, p = .043. LIMITATIONS: Small sample size and the use of a self-report questionnaire to assess depressive symptoms. CONCLUSIONS: Our findings support the possibility that OLP is an effective treatment for the relatively young population of depressed patients. Additional studies are warranted to explore the use of OLP in clinical practice.