Systemic diseases are rare and aetiologically diverse. They can affect a variety of organs; involvement of the small bowel occurs with varying degrees of frequency. The assignment of symptoms and findings (including endoscopic findings) to specific disease entities can be a formidable challenge. A diagnosis cannot be made from endoscopic findings alone but often needs biopsies, together with history, clinical and technical findings, and sometimes genetic testing. In very few cases, an intestinal involvement can be the initial manifestation of a systemic disease.Amyloid deposits, granulomatous diseases, multiple forms of vasculitis, collagen diseases, metabolic diseases, and rare hereditary syndromes can affect the small bowel. An overview of endoscopic images is presented in this chapter.