There is no clear data addressing the role of oxidative stress and proinflammatory mediators in acetic acid (AA)-induced colitis model. This study was aimed to study the effect of sulfasalazine (SLZ) on AA-induced colitis in rats. Rats were allocated into 3 groups: group 1: control, group 2: AA group (received 1 ml 4% acetic acid transrectaly single dose at 13th day), group 3: SLZ+AA group (recieved SLZ 250 mg/kg/day orally for 14 days and 1 ml 4% acetic acid transrectaly single dose at 13th day). Rats were sacrificed after 2 weeks. The colonic oxidative damage and inflammatory effects of AA were evaluated by measuring colonic levels of malonaldehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), histamine, interleukin-1β (IL-1β), interleukin-18 (IL-18) and histopathological assessment. Colitis induced by AA revealed statistically significant improvement in rats treated with SLZ compared with AA alone group. These results suggest that SLZ can protect against AA- induced colitis. SLZ effects rely, at least partially, on its antioxidant and anti-inflammatory effects.