Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an effective treatment for medically refractory essential tremor. We investigate ablation sites and potential tracts associated with optimal tremor control and side effects based on the analysis of 351 cases from three international hospitals. Lesions were segmented on day 1 thin-cut T2 axial images, mapped to standard Montreal Neurological Institute space, and used to derive probabilistic maps and tracts associated with tremor improvement and side effects. Lesioning of a specific subregion within the ventral intermediate nucleus and the cerebellothalamic tract was associated with optimal tremor improvements. Some lesion locations and tracts were associated with differential side effects. Overlaps with the optimal tremor improvement sites accounted for variance in clinical improvements in out-of-sample cases. Efficacy of this location was further confirmed by test-retest cases that underwent two MRgFUS procedures. We identify and validate a target area for optimal tremor control and sites of avoidance associated with side effects.