PURPOSE/OBJECTIVE(S): Stereotactic radiosurgery (SRS) to the ventral intermediate nucleus (VIM) of the thalamus has been used with success to manage tremor in select patients. Because of the high doses, small target, & required precision, a non-invasive stereotactic radiosurgery instrument has been the historical choice platform. Our institution recently developed a technique to replicate functional SRS GK dose distributions on a multi-leaf collimator (MLC)-equipped linear accelerator (LINAC) without cumbersome, inefficient cones. We deployed this technique & tested it in a prospective clinical trial of safety & efficacy of SRS thalamotomy for non-DBS candidate patients with medically refractory essential or Parkinsonian tremor. MATERIALS/METHODS: We quantified pre-treatment tremor according to FTM/PROMIS scores. We generated MPRAGE, FGATIR, diffusion-weighted tractographic, & resting-state fMRI sequences. We identified the VIM via both thalamic parcellation & classical stereotactic reference location, & targeted it to 130Gy dmax in a fashion dosimetrically equivalent to 4.5mm GK shot. We adjusted each target such that the 25Gy isodose line did not overlap the posterior limb of the capsule. We immobilized patients in a highly rigid thermoplastic mask. We delivered treatment with a LINAC with high-definition HDMLC & intrafraction optical surface monitoring (OSMS) to ensure patient immobility. We surveilled post-treatment imaging and tremor scores. RESULTS: We accrued 32 patients over 30 months. One withdrew, & one elected to pursue previously declined DBS. At submission, 24 of the 32 patients had ≥6-month follow-up. 23/24 (96%) exhibited clinically meaningful tremor reduction. Median maximum pre- & post-tremor reduction was 59.8% (range: 11 - 100%). Time to patient-reported tremor improvement ranged from 0.3 to 15 months. One patient experienced Grade 2, and none experienced Grade 3 or higher toxicity. CONCLUSION: Frameless, coneless MLC-based SRS thalamotomy on the LINAC is a safe, effective treatment. Proper implementation requires attentive involvement by an experienced movement disorder radiosurgery team. Data continue to mature, but current results anticipate congruence to historical GK controls. We have expanded the trial to allow 20 additional patients.