BACKGROUND: Major depression is a common mental disorder that substantially impairs quality of life and has high societal costs. Although psychotherapies have proven to be effective antidepressant treatments, initial response rates are insufficient and the risk of relapse and recurrence is high. Improvement of treatments is badly needed. Studying the mechanisms of change in treatment might be a good investment for improving everyday mental health care. However, the mechanisms underlying therapeutic change remain largely unknown. The objective of the current study is to assess both the effectiveness of two commonly used psychotherapies for depression in terms of reduction of symptoms and prevention of relapse on short and long term, as well as identifying underlying mechanisms of change. METHODS: In a randomised trial we will compare (a) Cognitive Therapy (CT) with (b) Interpersonal therapy (IPT), and (c) an 8-week waiting list condition followed by treatment of choice. One hundred eighty depressed patients (aged 18-65) will be recruited in a mental health care centre in Maastricht (the Netherlands). Eligible patients will be randomly allocated to one of the three intervention groups. The primary outcome measure of the clinical evaluation is depression severity measured by the Beck Depression Intenvory-II (BDI-II). Other outcomes include process variables such as dysfunctional beliefs, negative attributions, and interpersonal problems. All self-report outcome assessments will take place on the internet at baseline, three, seven, eight, nine, ten, eleven, twelve and twenty-four months. At 24 months a retrospective telephone interview will be administered. Furthermore, a rudimentary analysis of the cost-effectiveness will be embedded. The study has been ethically approved and registered. DISCUSSION: By comparing CT and IPT head-to-head and by investigating multiple potential mediators and outcomes at multiple time points during and after therapy, we hope to provide new insights in the effectiveness and mechanisms of change of CT and IPT for depression, and contribute to the improvement of mental health care for adults suffering from depression. TRIAL REGISTRATION: The study has been registered at the Netherlands Trial Register, part of the Dutch Cochrane Centre (ISRCTN67561918).