ObjectiveThe increased prevalence of major depressive disorder (MDD) amid the COVID-19 pandemic has resulted in substantial growth in online mental health care delivery. Compared to its in-person counterpart, online cognitive behavioral therapy (e-CBT) is a time-flexible and cost-effective method of improving MDD symptoms. However, how its efficacy compares to in-person CBT is yet to be explored. Therefore, the current study compared the efficacy of a therapist-supported, electronically delivered e-CBT program to in-person therapy in individuals diagnosed with MDD.MethodsParticipants (n= 108) diagnosed with MDD selected either a 12 week in-person CBT or an asynchronous therapist-supported e-CBT program. E-CBT participants (n= 55) completed weekly interactive online modules delivered through a secure cloud-based online platform (Online Psychotherapy Tool; OPTT). These modules were followed by homework in which participants received personalized feedback from a trained therapist. Participants in the in-person CBT group (n= 53) discussed sessions and homework with their therapists during one-hour weekly meetings. Program efficacy was evaluated using clinically validated symptomatology and quality of life questionnaires.ResultsBoth treatments yielded significant improvements in depressive symptoms and quality of life from baseline to post-treatment. Participants who opted for in-person therapy presented significantly higher baseline symptomatology scores than the e-CBT group. However, both treatments demonstrated comparable significant improvements in depressive symptoms and quality of life from baseline to post-treatment. e-CBT seems to afford higher participant compliance as dropouts in the e-CBT group completed more sessions on average than those in the in-person CBT group.ConclusionThe findings support e-CBT with therapist guidance as a suitable option to treat MDD. Future studies should investigate how treatment accessibility is related to program completion rates in the e-CBT vs. in-person group.Clinical Trial RegistrationClinicalTrials.GovProtocol Registration and Results System (NCT04478058);clinicaltrials.gov/ct2/show/NCT04478058.