We report the case of a patient with central nervous system Whipple's disease who developed the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The patient did not exhibit any gastrointestinal symptoms and initially was diagnosed based on neurologic findings and a duodenal biopsy that was positive forTropheryma whippeliiby the polymerase chain reaction. Radiologic involvement of the hypothalamus suggested Whipple's disease as the likely etiology of the syndrome of inappropriate antidiuretic hormone secretion. With antimicrobial therapy, the patient's serum sodium level and symptoms showed improvement.