Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors are representative agents for the chemoprevention of sporadic colorectal neoplasia. However, few reports have described the chemopreventive effects of such agents on colitis-associated tumorigenesis. To clarify whether treatment with the COX-2 inhibitor may reduce the risk of colitis-associated neoplasia, we investigated the effect of one such agent, etodolac, on tumorigenesis in the colitis-associated neoplasia model using p53-deficient mice treated with dextran sulfate sodium (DSS). The p53-/- mice were divided into four groups: i) treatment with DSS + etodolac, then after two cycles of DSS, the mice were given distilled water for 84 days. In addition, etodolac was administered three times a week at a dose of 10 mg/kg body weight throughout the experiment. ii) Treatment with two cycles of DSS only, followed by distilled water for 84 days. iii) Treatment with etodolac alone. iv) Distilled water alone was administered to the control group. The incidence of mice with neoplasia was 82.4% in the DSS + etodolac group and 100% in the DSS-alone group. No neoplasia was observed in the etodolac-alone and control groups. The mean (+/- SEM) number of total neoplasias per mouse was 1.29+/-0.2 in the DSS + etodolac group and 3.0+/-0.52 in the DSS-alone group, the inter-group difference being significant (p<0.01). There was no significant difference in the inflammation score between these two groups. These results showed that treatment with etodolac significantly reduced the occurrence of neoplasia, suggesting that this COX-2 inhibitor has chemopreventive activity against colitis-associated tumorigenesis.