Colorectal cancer is one of the leading causes of cancer deaths in both men and women in the world. However, colon cancer can be prevented to some extent by consumption of edible natural products with chemopreventive properties. Therefore, we investigated, whether edible mushroom Pleurotus ostreatus (PO) has chemopreventive effect on inflammation-associated colon carcinogenesis induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by dextran sodium sulfate (DSS). PO treatment, at both doses (100 and 500 mg/kg), significantly reduced by 50 and 78% the number of aberrant crypt foci and the multiplicity of colon neoplasms by 43 and 89%, respectively. However, incidence of colon tumors and high grade dysplasia was reduced by 50 and 63% only in the dose 500 mg/kg of PO, respectively. Colon shortening and dysplastic index was significantly reduced by PO treatment in dose-dependent manner. The immunohistochemistry of colons revealed that treatment with PO suppressed expression of cyclin D1, Ki-67, COX-2 and F4/80. In summary, our data suggest that PO may prevent inflammation-associated colon carcinogenesis with exposure to PhIP through combined modulatory mechanisms of inflammation and tumor growth via suppression of COX-2, F4/80, Ki-67 and cyclin D1 expression in mice.