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Abstract Background Major depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD. Methods In this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS [cTBS] to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS [iTBS] to the left DLPFC) delivered 5 days a week for 4–6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals. Discussion Comprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD. Trial registration The trial is registered on https://clinicaltrials.gov/ct2/home (#NCT04142996).