Background: Physical therapies are recommended for individuals who are insufficiently responsive to pharmacotherapy and psychotherapy. But most physical therapy needs to be done in a hospital, so finding a physical therapy that can be done at home is very meaningful. This study intends to explore the efficacy and safety of remote ischemic preconditioning (RIPC) as an add-on therapy for depression. Methods: A total of 60 major depressive disorder patients with inadequate response to escitalopram in this study were randomly assigned to sham or active RIPC group. The clinical symptoms, side-effects and physical examination were evaluated and recorded once every 2 weeks until the end of 8th week. The clinical symptoms were evaluated using the 16-item Quick Inventory of Depressive Symptomatology (Self-Report) (QIDS-16-SR) and the Generalized Anxiety Disorder 7-item scale (GAD-7). Side-effects included skin ecchymosis, risk of manic episodes, and RIPC-related serious adverse events. Physical examination included heart rate and blood pressure. Results: No significant difference in QIDS-16-SR and GAD-7 scores between the two groups was found at baseline, week 2, week 4, week 6 and week 8 (P > 0.05). There were no significant differences in heart rate and blood pressure (including systolic and diastolic blood pressure) at any time point between the active group and the sham group (P > 0.05). There were no manic or hypomanic episodes associated with the study. Conclusion: For depression patients with poor response to antidepressant therapy, the efficacy of RIPC as adjuvant therapy was not observed in this study. In general, RIPC adjuvant therapy is relatively safe, and has no significant effect on cardiovascular system, nor does it increase the risk of manic episode.