Objective: To evaluate feasibility, efficacy, and tolerability of Sudarshan Kriya yoga (SKY) as an adjunctive intervention in patients with major depressive disorder (MDD) with inadequate response to antidepressant treatment.Methods: Patients with MDD (defined by DSMIV-TR) who were depressed despite ≥ 8 weeks of antidepressant treatment were randomized to SKY or a waitlist control (delayed yoga) arm for 8 weeks. The primary efficacy end point was change in 17-item Hamilton Depression Rating Scale (HDRS-17) total score from baseline to 2 months. The key secondary efficacy end points were change in Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) total scores. Analyses of the intent-to-treat (ITT) and completer sample were performed. The study was conducted at the University of Pennsylvania between October 2014 and December 2015. Results: In the ITT sample (n = 25), the SKY arm (n = 13) showed a greater improvement in HDRS17 total score compared to waitlist control (n = 12) (−9.77 vs 0.50, P = .0032). SKY also showed greater reduction in BDI total score versus waitlist control (−17.23 vs −1.75, P = .0101). Mean changes in BAI total score from baseline were significantly greater for SKY than waitlist (ITT mean difference: −5.19; 95% CI, −0.93 to −9.34; P = .0097; completer mean difference: −6.23; 95% CI, −1.39 to −11.07; P = .0005). No adverse events were reported. Conclusions: Results of this randomized, waitlistcontrolled pilot study suggest the feasibility and promise of an adjunctive SKY-based intervention for patients with MDD who have not responded to antidepressants. Trial Registration: ClinicalTrials.gov identifier: NCT02616549 J Clin Psychiatry 2017;78(1):e59–e63 dx.doi.org/10.4088/JCP.16m10819 © Copyright 2016 Physicians Postgraduate Press, Inc.