We report here the efficacy of dietary antioxidants in combination with chemotherapy on tumor growth in the orthotopic COLO-205-green fluorescent protein (GFP) human colon cancer mouse model. The orthotopically-transplanted nude mice used for the study were randomly divided into 5 groups (A-E) after surgical orthotopic implantation (SOI) of tumor tissue. The following diets were given: Diet A, modified AIN-93M mature rodent diet with 4% fish oil; Diet B, modified AIN-93M which contains added antioxidants vitamin A, vitamin E, and selenium at levels present in the standard AIN-93M diet; Diet C, Diet A without added antioxidants vitamin A, vitamin E, or selenium; Diet D, Diet A with 5 times the amount of added antioxidants vitamin A, vitamin E, and selenium present in Diet B. Cisplatin, 7 mg/kg, was administered intraperitoneally on day 16 after SOI. Throughout the course of treatment, noninvasive whole-body imaging, based on the GFP expression of the tumor, permitted visualization of tumor progression. At sacrifice, the mean tumor weights showed significant statistical differences in all of the treated groups compared to the negative control (no cisplatin treatment) (p <or=0.001). The mean tumor weight showed a significant statistical difference between the Diet D combined with the cisplatin group compared to Diet B combined with cisplatin (p=0.038). Thus, we have demonstrated that Diet D is effective against tumor growth in combination with cisplatin in the fluorescent mouse model of colon cancer COLO-205 GFP. The results of the present study therefore indicate enhancement of cisplatin efficacy by high-dose antioxidants in combination with fish oil for colon cancer progression and suggests the design of clinical trials for this regimen.