The effective treatment of major depressive disorder remains one of the biggest public health challenges globally. For moderate to severe cases, pharmacotherapy often falls short, leading to treatment-resistant depression. Electroconvulsive therapy (ECT) has generally been considered the gold standard for severe cases of treatment-resistant depression. However, emerging evidence suggests that ketamine may serve as a promising alternative. Two relatively large noninferiority trials and three meta-analyses support the efficacy of both treatments but report contradictory findings regarding superiority. The authors discuss possible reasons underlying these discrepant findings, including variations in patient selection criteria, study outcome measures, treatment delivery, and site experience. Additionally, the authors examine the unique risk and benefit profiles of each treatment, highlighting patient-specific considerations. By evaluating the most recent evidence for the efficacy of ketamine versus ECT alongside key patient-specific factors, the authors aimed to guide clinicians in recommending the optimal treatment choice for each patient.