Whipple's disease (WD) is a rare systemic disease caused by infection with the recently identified actinomycetes, Tropheryma whippelii. The disorder affects mostly middle-aged men, and the major clinical features are weight loss, arthropathy, and diarrhea; other symptoms, caused by systemic infection, are not infrequent. The diagnosis is usually established by duodenal biopsy, which shows the pathognomonic periodic acid Schiff-positive infiltrates in the lamina propria. In addition, RT-polymerase chain reaction of tissue specimens can be used to verify the presence of T whippelii. In most cases, patients can be successfully treated by prolonged administration of antimicrobials, such as trimethoprim-sulfamethoxazole. The unusual chronic-relapsing course of the disease, the predisposition of middle-aged, HLA-B27-positive men for WD, and other characteristics of the disease imply that host factors are involved in the etiopathogenesis of WD. Indeed, it has been shown that patients with WD have suppressed delayed-type hypersensitivity responses in vivo and decreased in vitro T-cell responses, eg, to phytohemagglutinin and concanavalin A. In addition, serum-suppressor factors and shifts in T-cell subpopulations have been found. Perhaps most importantly, WD macrophages have a decreased ability to degrade intracellular microorganisms and patients have reduced numbers of circulating cells expressing CD11b, a cell adhesion and complement receptor molecule on macrophages involved in the activation of intracellular killing of pathogens. Most of those immunologic alterations also occur in patients with longstanding clinical remission, suggesting that this subtle host-defense defect plays an important role in disease pathogenesis.