Disorder-specific cognitive behavior therapy (DS-CBT) is effective at treating major depressive disorder (MDD) while transdiagnostic CBT (TD-CBT) addresses both principal and comorbid disorders by targeting underlying and common symptoms. The relative benefits of these two models of therapy have not been determined. Participants with MDD (n = 290) were randomly allocated to receive an internet delivered TD-CBT or DS-CBT intervention delivered in either clinician-guided (CG-CBT) or self-guided (SG-CBT) formats. Large reductions in symptoms of MDD (Cohen's d ≥ 1.44; avg. reduction ≥ 45%) and moderate-to-large reductions in symptoms of comorbid generalised anxiety disorder (Cohen's d ≥ 1.08; avg. reduction ≥ 43%), social anxiety disorder (Cohen's d ≥ 0.65; avg. reduction ≥ 29%) and panic disorder (Cohen's d ≥ 0.45; avg. reduction ≥ 31%) were found. No marked or consistent differences were observed across the four conditions, highlighting the efficacy of different forms of CBT at treating MDD and comorbid disorders.