BACKGROUND Ulcerative colitis is a relapsing inflammatory disorder of the colon. There is a need to explore the new treatments for this disorder. Theophylline, a competitive inhibitor of phosphodiesterase, is shown to have anti-inflammatory properties. However, the effect of theophylline on ulcerative colitis has not yet been investigated. The present study evaluated the effect of theophylline on acetic acid induced ulcerative colitis in rats. METHODS Colitis was induced by instillation of 2ml of acetic acid solution (3%). Colon samples were evaluated grossly and microscopically and assayed for myeloperoxidase (MPO) activity and proinflammatory cytokine concentrations. RESULTS Treatment with theophylline at the doses of 20 and 50mg/kg attenuated acetic acid induced ulcerative colitis as shown by improvement in body weight loss, macroscopic score, ulcer area, hematocrit and histopathological score. Theophylline treatment also reduced MPO activity and tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1 β) and interleukin 6 (IL-6) concentrations in inflamed colon. CONCLUSIONS Theophylline has a protective effect in acetic acid-induced ulcerative colitis which might be due to its anti-inflammatory activities. Therefore, theophylline has the potential to be used for successful treatment of ulcerative colitis.