A 50-year-old man presented with a 12 kg weight loss in 8 months. Upper gastrointestinal endoscopy findings showed strong erosion and diffuse bleeding in the duodenum. Histopathological findings showed PAS staining-positive macrophages consistent with Whipple's disease. He was treated with trimethoprim-sulfamethoxazole. His condition initially improved. However, during his 6-year course of treatment he developed a central nervous system relapse. Tropheryma whipplei DNA was detected by a polymerase chain reaction in his cerebrospinal fluid. This relapse was successfully treated with ceftriaxone sodium (CTRX). We considered that as initial therapy for Whipple's disease, it would be important to administer CTRX for at least a few months, due to its high translatability to CSF.