Abstract Background The general aim of this study was to investigate the effectiveness of blended Cognitive Behavioral Therapy (bCBT) as compared to Treatment as Usual (TAU) for depression in specialized routine mental healthcare in the Netherlands. We further explored a range of secondary outcome variables, including quality of life, clinical response, remission and reliable improvement, as well as clinical deterioration and potential negative effects of treatment. Methods n = 103 patients with Major Depressive Disorder were recruited as part of the E-COMPARED project, and randomly allocated to bCBT (n = 53) or TAU (n = 50). Measurements took place at baseline, 3-, 6- and 12-months follow-up. Treatment effects were analyzed using linear mixed-effects models for repeated measures. Results Depressive symptoms significantly declined and quality of life significantly improved over time in both bCBT and TAU during 12-months follow-up. No significant interaction effects between treatment group and assessment point were found. Likewise, there were no significant differences between the two treatment groups on secondary outcomes. Patients following bCBT went from severe to mild symptom severity, along with large within-group effects. Conclusion Applying bCBT in routine specialized mental health care seems promising, but is a relatively new form of treatment that is still under development and more research is needed. Clinical Trial Registration Netherlands Trials Register NTR4962. Registered on 5 January 2015.