AbstractDespite substantial advances in treatment and management strategies for major depression, less than 50% of patients respond to first-line antidepressant treatment or psychotherapy. Given the growing number of controlled studies of psychotherapy for treatment-resistant depression (TRD) and the preference for psychotherapy of depressed subjects as a treatment option, we conducted a meta-analysis and meta-regression analysis to investigate the effectiveness of psychotherapy for TRD. Seven different psychotherapies were studied in 21 trials that included a total of 25 comparisons. In three comparisons of psychotherapy v. treatment as usual (TAU) we found no evidence to conclude that there is a significant benefit of psychotherapy as compared with TAU. In 22 comparisons of add-on psychotherapy plus TAU v. TAU only, we found a moderate general effect size of 0.42 (95% CI 0.29–0.54) in favor of psychotherapy plus TAU. The meta-regression provided evidence for a positive association between baseline severity as well as group v. individual therapy format with the treatment effect. There was no evidence for publication bias. Most frequent investigated treatments were cognitive behavior therapy, interpersonal psychotherapy, mindfulness-based cognitive therapy, and cognitive behavioral analysis system of psychotherapy. Our meta-analysis provides evidence that, in addition to pharmacological and neurostimulatory treatments, the inclusion of add-on of psychotherapy to TAU in guidelines for the treatment of TRD is justified and will provide better outcomes for this difficult-to-treat population.