Backgrounds and Aims: The effect of cigarette smoking [CS] is ambivalent since smoking improves ulcerative colitis [UC] while it worsens Crohn's disease [CD]. Although this clinical relationship between inflammatory bowel disease [IBD] and tobacco is well established, only a few experimental works have investigated the effect of smoking on the colonic barrier homeostasis focusing on xenobiotic detoxification genes. Methods: A comprehensive and integrated comparative analysis of the global xenobiotic detoxification capacity of the normal colonic mucosa of healthy smokers [n = 8] and non-smokers [n = 9] versus the non-affected colonic mucosa of UC patients [n = 19] was performed by quantitative real-time polymerase chain reaction [qRT PCR]. The detoxification gene expression profile was analysed in CD patients [n = 18], in smoking UC patients [n = 5], and in biopsies from non-smoking UC patients cultured or not with cigarette smoke extract [n = 8]. Results: Of the 244 detoxification genes investigated, 65 were dysregulated in UC patients in comparison with healthy controls or CD patients. The expression of >= 45/65 genes was inversed by CS in biopsies of smoking UC patients in remission and in colonic explants of UC patients exposed to cigarette smoke extract. We devised a network-based data analysis approach for differentially assessing changes in genetic interactions, allowing identification of unexpected regulatory detoxification genes that may play a major role in the beneficial effect of smoking on UC. Conclusions: Non-inflamed colonic mucosa in UC is characterised by a specifically altered detoxification gene network, which is partially restored by tobacco. These mucosal signatures could be useful for developing new therapeutic strategies and biomarkers of drug response in UC.