Background and aims: Radiation colitis typically emerges during radiotherapy of intra-abdominal malignancies. While the underlying mechanism remains unclear, it is considered that free oxygen radicals act like cellular mediators to cause colonic damage. Apocynin (APO) prevents oxidative stress and apoptotic cell death by inhibiting NADPH oxidase, and preventing the formation of free oxygen radicals. The aim of the present study was to investigate the protective effect of APO, a strong antioxidant and antiinflammatory agent, on radiation induced colonic oxidative damage in rats.Materials and methods: Rats were randomly divided into four groups (n=8/group). Group I (control group); Group II (Group RAD) received a single dose of 800 cGy ionizing radiation to the whole abdomen with a linear accelerator (LINAC); Group III (Group APO) received a single dose of 20mg/kg of APO intraperitoneally for five days; Group IV (Group APO+RAD) received APO for five days before radiation exposure (similar to Group III), (similar to Group II).Results: APO treatment prior to radiation led to protection in the biochemical and histopathological parameters.Conclusions: Our study shows that APO treatment before radiation improves radiation induced colonic injury in rats, by decreasing oxidative stress and apoptosis.