Background: Major depressive disorder (MDD) is projected to rank second on a list of 15 major diseases in terms of burden in 2030. The contribution of MDD to disability and health care costs is largely due to its highly recurrent nature. Therefore, part of the efforts to reduce the disabling effects of depression should focus on preventing recurrence, especially in patients at high risk of recurrence. The best established effective psychological intervention is cognitive therapy, with indications for prophylactic effects after remission. Methods/Design: In this randomized controlled trial (cost-) effectiveness of Preventive Cognitive Therapy (PCT) after response to Acute Cognitive Therapy (A-CT) will be evaluated in comparison with Treatment As Usual (TAU). Remitted patients that responded to A-CT treatment with at least two previous depressive episodes will be recruited. Randomization will be stratified for number of previous episodes. Follow-ups are at 3, 6, 12 and 15 months. The primary outcome measure will be the time to relapse or recurrence of depression meeting DSM-IV criteria for a major depressive episode on the Structured Clinical Interview for DSM-VI Axis I Disorders (SCID-I). Costs will be measured from a societal perspective. Discussion: This study is the first to examine the addition of PCT to TAU, compared to TAU alone in patients that recovered from depressive disorder with A-CT. Alongside this effect study a cost effectiveness analysis will be conducted. Furthermore, the study explores potential moderators to examine what works for whom. Trial registration: Netherlands Trial Register (NTR): 2599, date of registration: 11-11-2010.