Background: Depressive disorders are highly prevalent and result in negative consequences for both patients and society. It is therefore important that these disorders are treated adequately. However, due to increased demand for mental healthcare and subsequent increased costs, it would be desirable to reduce costs associated with major depressive disorder while maintaining or improving the quality of care within the healthcare system. Introducing evidence-based online self-help interventions in mental healthcare might be the way to maintain clinical effects while minimizing costs by reducing the number of face-to-face sessions. This study aims to evaluate the clinical and economical effects of a guided online self-help intervention when offered to patients with major depressive disorder on a waiting list for psychotherapy in specialized mental health centers (MHCs).Methods: Patients at mental health centers identified with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnosis of major depression who are awaiting face-to-face treatment are studied in a randomized controlled trial. During this waiting list period, patients are randomized and either (1) receive an internet-based guided self-help treatment or (2) receive a self-help book. The 5-week internet-based guided self-help intervention and the self-help booklet are based on problem solving treatment. After the intervention, patients are allowed to start regular face-to-face treatment at MHCs. Costs and effects are measured at baseline, after the intervention at 6 to 8 weeks, 6 months and 12 months. The primary outcome measure is symptoms of depression. Secondary outcome measures are diagnosis of depression, number of face-to-face sessions, absence of work and healthcare uptake in general. Additional outcome measures are anxiety, insomnia, quality of life and mastery. Discussion: This study evaluates the effectiveness and cost effectiveness of internet-based guided self-help in patients at specialized mental health centers. The aim is to demonstrate whether the introduction of internet-based self-help interventions in regular mental healthcare for depressive disorders can maintain clinical effects and reduce costs. Strengths and limitations of this study are discussed. Trial registration: Netherlands Trial Register NTR2824. © 2013 Kenter et al.; licensee BioMed Central Ltd.