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Background With nearly one-third of patients with major depressive disorder being resistant to available antidepressants, there is a need to develop new treatments for this population. Stellate ganglion block (SGB) is a procedure used to block sympathetic input to the central autonomic system; it has been administered to treat several conditions, including pain. Recently, indications for SGB have extended and the potential benefits for psychiatric disorders are under investigation. Methods The Local Injection For Treating Mood Disorders (LIFT-MOOD) study investigated the feasibility of a trial of 2 right-sided injections of bupivacaine 0.5% (7 mL) at the stellate ganglion in participants with treatment-resistant depression (TRD) using a randomized, placebo-controlled, pilot trial. Ten participants were randomized in a 1:1 allocation to receive active treatment or placebo (saline). Primary feasibility outcomes included recruitment rate, withdrawal, adherence, missing data, and adverse events. As a secondary, exploratory objective, we explored the efficacy of SGB in improving symptoms of depression by calculating the change in scores from baseline to follow-up on day 42 for each treatment group. Results The recruitment rate was reasonable and sufficient, retention and adherence were high, missing data were low, and adverse events were mild and temporary. Both treatment groups demonstrated decreases in Montgomery-Åsberg Depression Rating Scale scores, compared to baseline, by the end of the study. Conclusion This study supports the feasibility of a confirmatory trial of SGB in participants with TRD. Conclusions regarding efficacy cannot be made based on this preliminary study due to the small number of participants who completed active treatment. Larger-scale randomized controlled trials with long-term follow-ups and alternate sham procedures are needed to assess the efficacy and duration of symptom improvement with the use of SGB in TRD.