Abstract: Background: Colorectal cancer is a leading cause of cancer-related death, and inflammatory bowel disease is a risk factor for this malignancy. We previously reported colon cancer chemoprevention potential using American ginseng in a xenograft mice model. However, the nude mouse model is not a gut-specific colon carcinogenesis animal model.Methods: In this study, an experimental colitis and colitis-associated colorectal carcinogenesis mouse model, chemically induced by AOM/DSS, was established and the effects of oral American ginseng were evaluated. The contents of representative ginseng saponins in the extract were determined.Results: Our data demonstrated that American ginseng significantly reduced experimental colitis measured by the disease activity index scores. This suppression of the experimental colitis was not only evident during DSS treatment, but also very obvious after the cessation of DSS, suggesting that the ginseng significantly promoted recovery from the colitis. Consistent with the anti-inflammation data, we showed that ginseng very significantly attenuated AOM/DSS-induced colon carcinogenesis by reducing colon tumor number and tumor load. The ginseng also effectively suppressed DSS induced pro-inflammatory cytokines activation using ELISA array, in which 12 pro-inflammatory cytokine levels were assessed, and this effect was supported subsequently by real-time PCR data.Conclusion: Our results suggested that American ginseng, as a candidate of botanical-based colon cancer chemoprevention, should be further investigated for its potential clinical utility.