Whipple's disease is a chronic systemic illness, the optimal treatment of which remains poorly defined. In our analysis of a 30-year, 29-patient experience with Whipple's disease at the Mayo Clinic, the frequent initial manifestations of diarrhea, weight loss, arthritis, and lymphadenopathy correlated with findings reported previously by other investigators. Antibiotic therapy yielded rapid symptomatic and biochemical improvement, and histologic changes in the small bowel occurred subsequently. Despite antimicrobial therapy, relapses in patients with Whipple's disease are common, and the central nervous system is considered the most serious site of involvement for recurrence. Administration of an antibiotic agent that is able to cross the blood-brain barrier may be more important in preventing relapse than prolonged duration of initial antimicrobial therapy.