Objective: To evaluate the safety and efficacy of unilateral Gamma Knife thalamotomy (GKT) for treatment of severe tremor with a prospective blinded assessment. Methods: Fifty patients (mean age: 74.5 years; 32 men) with severe refractory tremor (36 essential, 14 parkinsonian) were treated with unilateral GKT. Targeting of the ventral intermediate nucleus (Vim) was achieved with Leksell Gamma Knife with a single shot through a 4-mm collimator helmet. The prescription dose was 130 Gy. Neurologic and neuropsychological assessments including a single-blinded video assessment of the tremor severity performed by a movement disorders neurologist from another center were performed before and 12 months after treatment. MRI follow-up occurred at 3, 6, and 12 months. Results: The upper limb tremor score improved by 54.2% on the blinded assessment (p , 0.0001). All tremor components (rest, postural, and intention) were improved. Activities of daily living were improved by 72.2%. Cognitive functions remained unchanged. Following GKT, the median delay of improvement was 5.3 months (range 1–12 months). The only side effect was a transient hemiparesis associated with excessive edema around the thalamotomy in one patient. Conclusion: This blinded prospective assessment demonstrates that unilateral GKT is a safe and efficient procedure for severe medically refractory tremor. Side effects were rare and transient in this study.