A 72-year-old man presented with a 6-month history of dysphagia, fatigue, 60-lb weight loss, and central nervous system (CNS) deficits. Diffusion-weighted magnetic resonance imaging (MRI) of the brain showed mildly elevated nonrestricted apparent diffusion coefficients in the middle cerebellar peduncles, and magnetic resonance spectroscopy (MRS) showed decreased N-acetylaspartate and creatine with increased choline. Diffusion-weighted MRI and MRS offer noninvasive methods to help evaluate in vivo physiologic changes of CNS involvement in Whipple disease.