This report describes a patient who presented with fever, weight loss, diarrhea, and adenopathy. At the time of presentation he had a 28-year history of unusually severe destructive polyarthritis. Duodenal biopsy revealed periodic acid–Schiff–positive macrophages. Polymerase chain reaction studies showed positivity for Tropheryma whipplei in synovial fluid, synovial tissue, and lymph node specimens, and Whipple's disease was diagnosed. T whipplei was successfully cultivated from the synovial fluid by both cell culture and axenic culture. This strain (named ART1) was subcultured and subsequently established and genotyped. Antibiotic treatment was instituted in the patient, after which his symptoms remitted. These findings show for the first time that Whipple's arthritis may be, at least in some cases, a septic arthritis.