Introduction. Major depressive disorder (MDD) is a prevalent, debilitating and disabling disorder, and its prevalence is increasing. Antidepressants (AD), cognitive-behavioral therapy (CBT) and behavioral activation (BA) are the main treatments for MDD. Trial-based cognitive therapy (TBCT) addresses and restructures dysfunctional negative core beliefs (CBs) and is a novel and promising approach. Objective. The aim of this study was to compare the efficacy of TBCT, BA and treatment as usual (TAU) in the treatment of MDD. Methods. A total of 76 patients with MDD were randomized into 1 of 3 groups and evaluated at baseline, after 6 weeks and at week 12 (final evaluation). The primary outcome was changing in HAM-D scores, and the secondary outcomes included scores on the BDI, CD-Quest, Sheehan Disability Scale (SDS) and WHOQOL. Results. Both TBCT and BA (which also included AD) were different from TAU (which included antidepressants alone) in reducing the HAM-D and BDI scores and other measures. TBCT and BA were different from TAU in the reduction of disability in SDS and WHOQOL physical domain scores. Besides limited by a small sample size, the dropout rate in the TAU arm was higher, and only 10 patients completed the 3 evaluations. Conclusion. This trial provides evidence that TBCT and BA combined with antidepressants were more efficacious than the TAU (drug alone) in reducing the severity of depressive symptoms and disability, showing that this combination can be useful for clinical practice.