Any hypothesis on the cause of ulcerative colitis must account for genetic influences, geographic and ethnic variations, effects of smoking and oral contraception, anatomical distribution, the relapsing and remitting nature of the disease, and association with primary sclerosing cholangitis. This hypothesis proposes that ulcerative colitis is caused by a reactive xenobiotic metabolite which is conjugated before excretion into bile. The amount of metabolite produced is determined by exposure to its parent compound, by the inherited pattern of metabolism, and by inhibition and induction of enzymes catalysing alternative pathways. Deconjugation by bacteria within the colonic lumen releases the reactive metabolite, damaging the colonic epithelial barrier and exposing the mucosal immune system to luminal contents. Biliary epithelial damage by the metabolite leads to an immune response in those individuals carrying appropriate HLA molecules, thereby initiating an inflammatory process within the biliary tree.