BACKGROUND: 5-Lipoxygenase products play a part in inflammatory response. AIMS: The effect of intracolonic administration of zileuton (a 5-lipoxygenase inhibitor) on colonic damage and eicosanoid local release was assessed in a rat model of colitis. METHODS: Ninety rats with trinitrobenzenesulphonic acid induced colitis were randomised to receive placebo, 5-aminosalicylic acid (50 mg/kg), or zileuton (50 mg/kg) intracolonically for four weeks. Local eicosanoid release was monitored by intracolonic dialysis throughout the study. The colon was removed for macroscopic and histological assessment at weeks 1, 2, and 4 after colitis induction in 10 rats of each group. RESULTS: Zileuton significantly reduced macroscopic damage score after four weeks of treatment in comparison with the other two groups (p = 0.034). In addition, zileuton administration significantly increased the intracolonic release of both thromboxane B2 at week 1 (p = 0.05) and prostaglandin E2 at weeks 2 and 4 (p < 0.05). Zileuton and 5-aminosalicylic acid decreased leukotriene B4 release by 90% at day 3. CONCLUSIONS: Intracolonic zileuton, compared with 5-aminosalicylic acid and placebo, seems to improve the course of the disease in a model of chronic colitis. This effect may be related to an increased and maintained production of prostaglandin E2 together with inhibition of leukotriene B4 synthesis.