Magnetic resonance-guided focused ultrasound (MRgFUS) trials targeting the anterior limb of the internal capsule have shown promising results. We evaluate the long-term safety and efficacy of MRgFUS capsulotomy in patients with obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). This phase I single center open label study recruited treatment-resistant OCD and MDD. Outcomes were measured 6mo, 12mo, and 18-24months (long-term) after MRgFUS capsulotomy. Neuropsychological testing and neuroimaging were conducted at baseline and 12mo postoperatively. The primary outcome was safety. The secondary outcome was clinical response, defined for OCD as ≥35% improvement in Yale-Brown obsessive-compulsive scale (YBOCS) scores, and for MDD as a ≥50% reduction in the Hamilton Depression Rating Scale (HAMD-17) scores, compared to baseline. No serious adverse effects were registered. In patients with OCD (n=15), baseline YBOCS scores (31.9±1.2) were significantly reduced by 23% (p=0.01) at 6mo and 35% (p<0.0001) at 12mo. In patients with MDD (n=12), a 26% and 25% non-significant reduction in HAMD-17 scores (baseline 24.3±1.2) was observed at 6mo and 12mo, respectively. Neuropsychological testing revealed no negative effects of capsulotomy. In the OCD and MDD cohorts we found a correlation between clinical outcome and lesion laterality, with more medial left (OCD, p=0.08) and more lateral right (MDD, p<0.05) placed lesions being respectively associated with a stronger response. In the MDD cohort, more ventral tracts appeared to be associated with a poorer response. MRgFUS capsulotomy is safe in patients with OCD and MDD and particularly effective in the former population.