Diffuse or focal white matter hyperintensity lesions on MRI have been reported in only a few patients with Hashimoto's encephalopathy (HE), and anti-TPO antibody level is high in most cases. We report a 59-year-old woman who presented with acute onset of disorientation with confusion. Anti-thyroglobulin antibody was detected in high titer, although anti-TPO antibody titer was not high. Thyroid sonography and biopsy revealed Hashimoto's thyroiditis. Initial fluid-attenuated inversion recovery (FLAIR) image and diffusion-weighted imaging (DWI) revealed ill-defined, diffuse, high-signal intensity lesions on the deep white matters and globus pallidus. Brain SPECT showed significant hypoperfusion in both basal ganglia (especially globus pallidus), frontal and temporal lobes. With the impression of HE, the patient was treated on a high-dose steroid. Over the next 15 weeks, her cognition improved to a nearly normal state and the MRI findings on DWI and FLAIR showed resolution paralleling her clinical improvement. Our case illustrates the peculiar changes in the MR findings, especially in DWI, with hypoperfusion on brain SPECT in patients with HE and allows for a greater understanding of the pathophysiology of HE.