We report a case of Whipple disease in a 55-year-old woman who presented with arthralgia, weight loss, and lymphadenopathy. Tropheryma whippleii bacilli were identified in the mesenteric lymph nodes by diastase-resistant periodic acid-Schiff stain and confirmed by electron microscopy. Retrospectively, previous biopsy specimens from the duodenum and right axillary lymph node of this patient, which were initially considered to demonstrate reactive changes, also showed features consistent with involvement by Whipple disease. At the time of presentation, a large kappa-restricted monoclonal B-cell population with the phenotype CD20+CD19+CD5-CD10- was identified in the patient's peripheral blood, lymph nodes, and bone marrow by flow cytometry study. The monoclonality of the mesenteric lymph node B cells was confirmed by immunohistochemical stain for kappa chain after antigen retrieval and also by polymerase chain reaction with the primer set targeting FR2-V(H). Routine cytogenetic study failed to reveal any chromosomal abnormalities, and polymerase chain reaction for Bcl-2 major and minor breakpoint cluster of t(14:18) was not detected. The monoclonal B cells have persisted in blood for the entire follow-up period (10 months). The possibility of reactive monoclonal B-cell proliferation versus Whipple disease-related B-cell lymphoma is discussed.