The gastrointestinal tract may be of major clinical or diagnostic importance in fever of unknown origin. To the classical diseases in this sense belong very different diseases as Whipple's disease, Familiar Mediterranean Fever, isolated mesenterial vasculitis, and manifestations of immune reconstitution inflammatory disease, but also unusual manifestations of otherwise easily recognized diseases like special forms of celiac disease, or inflammatory bowel disease. Endoscopical techniques to obtain biopsies for diagnostic procedures are frequently crucial to solve the diagnostic puzzle. In some cases the bioptic material may not be sufficient to reach a diagnosis and further surgical intervention is necessary (intestinal lymph-nodes or bowel resections) to acquire enough tissue for a definite diagnosis. Nevertheless using these different approaches in most cases of fever of unknown origin the underlying cause can be identified which for many patients means not more or less than significant improvement or even survival.