BackgroundMajor depressive disorder is a leading cause of disease burden worldwide, indicating the importance of effective therapies. Outcome studies have shown overall efficacy of different types of psychotherapy across groups, yet large variability within groups. Although patient characteristics are considered crucial in understanding outcome, they have received limited research attention. This trial aims at investigating the interaction between therapeutic approach (pre-structured versus explorative) and the personality style of patients (dependent versus self-critical), which is considered a core underlying dimension of depressive pathology.Methods/designThis study is a pragmatic stratified (dependent and self-critical patients) parallel trial with equal randomization (allocation 1:1) conducted in Flanders, Belgium. One hundred and four patients will be recruited and randomized to either 16–20 sessions of cognitive behavioral therapy for depression (pre-structured approach) or 16–20 sessions of short-term psychodynamic psychotherapy for depression (explorative approach) conducted by trained psychotherapists in private practices. The primary outcome is the severity of depression as measured by the Hamilton Rating Scale for Depression at completion of therapy. Secondary outcome measures include self-reported depressive and other symptoms, interpersonal functioning, idiosyncratic complaints, and the presence of the diagnosis of depression. Additional measures include biological measures, narrative material (sessions, interviews), and health care costs.DiscussionThis trial presents the test of an often-described, yet hardly investigated interaction between important personality dimensions and therapeutic approach in the treatment of depression. Results could inform therapists on how to match psychotherapeutic treatments to specific personality characteristics of their patients.Trial registrationIsrctn.com, ISRCTN17130982. Registered on 2 February 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-1867-x) contains supplementary material, which is available to authorized users.