Abstract Whipple’s disease is an uncommon infection caused by the actinomycete Tropheryma whipplei, most commonly diagnosed when overt small intestinal disease leads to malabsorption, but with protean other clinical manifestations (e.g. systemic, neurological, or cardiological). Diagnosis usually depends upon demonstration of classical histological features in the small intestine, and positive identification of T. whipplei DNA by polymerase chain reaction. Treatment is with antibiotics, initially doxycycline and hydroxychloroquine followed by long-term therapy with doxycycline. Clinical improvement occurs within a few weeks, but prolonged treatment for at least a year is recommended. Relapse can occur, even after many years, especially when progressive central nervous system disease occurs in the absence of other systemic manifestations.