Substantial evidence suggests a negative association between cigarette smoking and the incidence and severity of ulcerative colitis, a common human inflammatory bowel disease. Nicotine has been implicated in this association. The detection of nicotinic acetylcholine receptors in colonic epithelium, the primary tissue affected in ulcerative colitis, suggests a role for these receptors in the beneficial effect of nicotine on colonic inflammation. Using an animal model, we demonstrate for the first time that alpha5 nicotinic acetylcholine receptor knockout mice have significantly more severe experimental colitis than wild-type controls and that nicotine significantly ameliorates its course when compared with wild-type controls. These findings suggest that alpha5-containing nicotinic acetylcholine receptors participate in the modulation of colitis in mice, but other nicotinic acetylcholine receptor subunits also mediate the antiinflammatory effects of nicotine.