Inflammatory bowel disease (IBD) is characterised by episodes of relapse and periods of remission. However, the clinical features, such as abdominal pain, diarrhoea, and rectal bleeding, are not specific. Therefore, the differential diagnosis can include a broad spectrum of inflammatory or infectious diseases that mimic IBD, as well as others that might complicate existing IBD. In this Review, we provide an overview of ileocolitis of diverse causes that are relevant in the differential diagnosis of IBD. We highlight the importance of accurate patient profiling and give a practical approach to identifying factors that should trigger the search for a specific cause of intestinal inflammation. Mimics of IBD include not only infectious causes of colitis-and particular attention is required for patients from endemic areas of tuberculosis-but also vascular diseases, diversion colitis, diverticula or radiation-related injuries, drug-induced inflammation, and monogenic diseases in very-early-onset refractory disease. A superinfection with cytomegalovirus or Clostridium difficile can aggravate intestinal inflammation in IBD, especially in patients who are immunocompromised. Special consideration should be made to the differential diagnosis of perianal disease.