Whipple disease is a rare infectious disorder with multiorgan manifestations and a widely varied clinical presentation. Involvement of the small intestine with resultant malabsorption is a classic finding, although extraintestinal manifestations such as fever and arthralgias may precede gastrointestinal symptoms by many years. We describe a 63-year-old man in whom Whipple disease was diagnosed 22 years after his initial presentation (36 years after symptom onset) with lymphadenopathy, when a biopsy yielded nonnecrotizing granulomas. His recent symptoms included persistent fatigue, weight loss, fever, and arthralgias. Endoscopic biopsy specimens from the distal duodenum showed features consistent with Whipple disease, and Tropheryma whippelii DNA was detected in both the small bowel biopsy specimen and the blood specimen by polymerase chain reaction and DNA probe hybridization. His symptoms resolved with long-term co-trimoxazole therapy. We discuss the protean manifestations of Whipple disease, the difficulties in clinical diagnosis, and the recent advances in the molecular diagnosis of this disorder.