Adult-onset leukoencephalopathies with increased cerebral volume can present a potentially challenging diagnosis for the pathologist. We present the case of a patient with a rare adult-onset disease called Leukoencephalopathy with cerebral Calcifications and Cysts (LCC). A 55-year-old woman with a history of morning headaches, mild memory loss, diabetes, and hypertension presented to the emergency department with acute onset altered mental status. CT scan revealed multiple small hypodense lesions in the white matter with calcifications in the bilateral cerebral hemispheres, basal ganglia, pons, and cerebellar hemispheres. MRI showed multiple complex/hemorrhagic cystic lesions with partial enhancement in addition to calcifications bilaterally in the frontotemporal white matter, pons, and cerebellar hemispheres, and diffuse white matter signal abnormality. The differential diagnosis included chronic infection, chronic thromboembolic disease, and neoplasm. The biopsy revealed extensive geode-like mineralization as well as smaller calcifications (calcospherites) with associated sclerosis, Rosenthal fibers, angiomatous proliferation of blood vessels with thrombosis and microbleeds. We discuss the differential diagnosis, radiologic and detailed histologic features of LCC.