Importance: Patients with treatment-resistant depression (TRD) do not respond sufficiently to several consecutive treatments for major depressive disorder. Deep brain stimulation (DBS) is a promising treatment for these patients, but presently placebo effects cannot be ruled out. O. Objective: To assess the efficacy of DBS of the ventral anterior limb of the internal capsule (vALIC), controlling for placebo effects with active and sham stimulation phases. Design, Setting, and Participants: Twenty-five patients with TRD from 2 hospitals in the Netherlands were enrolled between March 22, 2010, and May 8, 2014. Patients first entered a 52-week open-label trial during which they received bilateral implants of 4 contact electrodes followed by optimization of DBS until a stable response was achieved. A randomized, double-blind, 12-week crossover phase was then conducted with patients receiving active treatment followed by sham or vice versa. Response and nonresponse to treatment were determined using intention-to-treat analyses. INTERVENTIONS Deep brain stimulation targeted to the vALIC. Main Outcomes and Measures: The change in the investigator-rated score of the 17-item Hamilton Depression Rating Scale (HAM-D-17) was the main outcome used in analysis of the optimization phase. The primary outcome of the crossover phase was the difference in the HAM-D-17 scores between active and sham DBS. The score range of this tool is 0 to 52, with higher scores representing more severe symptoms. Patients were classified as responders to treatment (≥50% decrease of the HAM-D-17 score compared with baseline) and partial responders (≥25 but <50% decrease of the HAM-D-17 score). RESULTS Of 25 patients included in the study, 8 (32%)were men; the mean (SD) age at inclusionwas 53.2 (8.4) years. Mean HAM-D-17 scores decreased from 22.2 (95%CI, 20.3-24.1) at baseline to 15.9 (95%CI, 12.3-19.5) (P = .001), Montgomery-Åsberg Depression Rating Scale scores from 34.0 (95%CI, 31.8-36.3) to 23.8 (95%CI, 18.4-29.1) (P < .001), and Inventory of Depressive Symptomatology-Self-report scores from from 49.3 (95%CI, 45.4-53.2) to 38.8 (95%CI, 31.6-46.0) (P = .005) in the optimization phase. Following the optimization phase, which lasted 51.6 (22.0)weeks, 10 patients (40%)were classified as responders and 15 individuals (60%) as nonresponders. Sixteen patients entered the randomized crossover phase (9 responders [56%], 7 nonresponders [44%]). During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6 [95%CI, 9.8-17.4]) than during sham DBS (23.1 [95%CI, 20.6-25.6]) (P < .001). Serious adverse events included severe nausea during surgery (1 patient), suicide attempt (4 patients), and suicidal ideation (2 patients). Conclusions and Relevance: Deep brain stimulation of the vALIC resulted in a significant decrease of depressive symptoms in 10 of 25 patients and was tolerated well. The randomized crossover design corroborates that vALIC DBS causes symptom reduction rather than sham.