Obsessive compulsive disorder (OCD) and major depressive disorder (MDD) are common, often refractory, neuropsychiatric conditions for which new treatment approaches are urgently needed. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel surgical technique permitting incisionless ablative neurosurgery. We examined the safety profile, clinical response, and imaging correlates of MRgFUS bilateral anterior capsulotomy in patients with refractory obsessive compulsive disorder (OCD, N = 6) and major depressive disorder (MDD, n = 6). There were no serious adverse events. Nonserious adverse events included headaches and pin-site swelling in 7/12 patients. The response rate was 4/6 and 2/6 in the OCD and MDD cohorts respectively. To delineate the white-matter tracts impacted by capsulotomy, a normative diffusion MRI-based structural connectome was used, revealing tracts terminating primarily in the frontal pole, medial thalamus, striatum, and medial-temporal lobe. Positron emission tomography (PET) analysis (nine subjects) revealed widespread decreases in metabolism bilaterally in the cerebral hemispheres at 6 months post treatment, as well as in the right hippocampus, amygdala, and putamen. A pretreatment seed-to-voxel resting-state functional magnetic resonance imaging (rs-fMRI) analysis (12 subjects) revealed three voxel clusters significantly associated with eventual clinical response. MRgFUS capsulotomy appears to be safe, well tolerated, and according to these initial results, may be an important treatment option for patients with refractory OCD and MDD. MRgFUS capsulotomy results in both targeted and widespread changes in neural activity, and neuroimaging may hold potential for the prediction of outcome.