Studies in pigs and rats were undertaken to explore further the role of leukotrienes following administration of NSAIDs on the development of gastrointestinal damage. Increased leukotriene C₄ production occurred in the gastric circulation in the early stages after administration of a single dose of indomethacin (10 mg/kg i.g.) to pigs. Gastric and intestinal mucosal lesions by NSAIDs were prevented by both prior (2–5 h)+0.25 or 0 h oral dosing of the 5-lipoxygenase inhibitor, MK-886, but not when only one of these doses was given. These results show the importance of enhanced peptidoleukotriene production in relation to microvascular damage from cyclooxygenase inhibition by NSAIDs.