Whipple disease is a rare disease caused by infection with the bacterium Tropheryma whippelii. Humans are the only known host for the infection. The signs of systemic infection include gastrointestinal problems, weight loss, and arthritis. Signs of central nervous system infection include cognitive changes, supranuclear gaze palsy, altered level of consciousness, and movement disorders. The diagnosis is based on clinical findings as well as microscopic examination of biopsy specimens and, more recently, polymerase chain reaction (PCR) analysis, which has high sensitivity and specificity. Although the organism historically has been difficult to culture, several recent attempts have been successful. Antibiotic treatment is recommended for 1 year while monitoring the clinical signs and cerebrospinal fluid PCR results.