Background: MRI-guided focused US thalamotomy of ventral intermediate nucleus of the thalamus is a treatment for tremor disorders. Purpose: To evaluate white matter integrity before and after thalamotomy and its correlation with clinical outcome. Materials and Methods: Participants with essential tremor (ET) or Parkinson disease (PD) undergoing thalamotomy were prospectively recruited between March 2016 and October 2018. Tremor and quality of life were assessed before, 1 month after, and 6 months after thalamotomy. Participants underwent T1-weighted, T2-weighted fluid-attenuated image recovery, and diffusion-tensor MRI before and 1 day, 7210 days, 123 months, and 6 months or longer after treatment. Diffusivity and fiber tractography measures were calculated. Repeated measures analysis of variance with post hoc paired t test and Skillings-Mack test with post hoc Wilcoxon signed-rank test were used for normally and nonnormally distributed data, respectively, and Bonferroni method corrected for multiple comparisons. Results: Twenty-two study participants with ET (mean age, 72 years 6 6 [standard deviation]; 14 men), 17 participants with PD (mean age, 65 years 6 8; 13 men), and a replication set of 17 participants with ET (mean age, 73 years 6 6; 10 men) were evaluated. Long-term damage was found in the ablated core (mean fractional anisotropy [FA] at baseline, 0.41 6 0.10, and at ≥6 months, 0.23 6 0.09; P , .001) and thalamus to red nucleus tract (mean number of tracts at baseline, 1663, and at ≥6 months, 1070; P = .003). Negative correlation was observed between motor thalamus FA 1 day after ablation and tremor improvement (ET: R = 20.52 [P = .03]; PD: R = 20.61 [P = .003]). Better tremor relief in ET was associated with lower fractional anisotropy before treatment (R = 20.5; P = .02). Conclusion: MRI-guided focused US thalamotomy resulted in short- and long-term white-matter changes. Diffusion-tensor imaging provided evidence for long-term damage in the ablation core and in the thalamus and red nucleus tract, and a correlation between preablation fractional anisotropy in the motor thalamus and clinical outcome.