A 37-year-old man developed encephalopathy with prominent eosinophilia. Magnetic resonance imaging (MRI) revealed multiple T2-weighted high signal intensity lesions with dimeglumine gadopentetate (Gd-DTPA) enhancement on T1-weighted images, which were distributed in the cerebral cortex, thalamus, deep white matter and cerebellum. He was diagnosed as having systemic mastocytosis on the basis of proliferating mast cells in the bone marrow and peripheral eosinophilia. Following steroid administration, there was a rapid improvement of his symptoms and laboratory data. To our knowledge, this was the first reported case of systemic mastocytosis provoking encephalopathy with serial MRI findings.