Background <p>This study aims to evaluate the clinical effectiveness and feasibility of a novel bilateral sequential accelerated theta-burst stimulation (BS-aTBS) protocol in treatment-resistant depression (TRD) patients, compared to a standard intermittent TBS (a-iTBS) protocol.</p> Methods <p>In this randomized controlled clinical trial, 94 TRD patients were randomly assigned to receive either BS-aTBS (<i>n</i> = 46) or a-iTBS (<i>n</i> = 48). Both groups delivered 10 daily TBS sessions (1800 pulses/session) for 5 consecutive days. The primary outcome was score on the 24-item Hamilton Depression Rating Scale (HDRS-24) after treatment, normalized to baseline (week 0).</p> Results <p>Both BS-aTBS and a-iTBS protocols significantly reduced HDRS-24 scores by week 1 (65.52% vs. 54.32%, <i>p</i> = 0.008) and week 5 (77.10% vs. 67.77%, <i>p</i> = 0.006), and the BS-aTBS group showed significantly greater symptom improvement at both time points. Compared to a-iTBS, the BS-aTBS yielded higher response rates at week 1 (78.26% vs. 58.33%, <i>p</i> = 0.038) and week 5 (93.48% vs. 77.08%, <i>p</i> = 0.026), and elicited greater alleviation for anxiety and suicidal ideation at week 5. Moreover, clinical improvement on sleep quality and cognitive abilities was larger in the BS-aTBS group, and the effects on anhedonia and alexithymia were comparable between the two protocols. No serious adverse events were observed.</p> Conclusions <p>The BS-aTBS protocol provided rapid and well-tolerated antidepressant effects in TRD patients lasting for 1&#xa0;month, with additional benefits for anxiety and suicidal ideation. Considering its clinical advantages and shortened treatment time, the BS-aTBS may serve as a promising treatment protocol for TRD patients with high feasibility and efficiency.</p> Trial registration <p>This trial was registered at Chinese Clinical Trial Registry (ChiCTR2400091459).</p>