To investigate the pathogenesis of indomethacin-induced gastric mucosal injury, vascular injury was examined in the rat using Evans blue and monastral blue vascular tracers. Extravasation of intravenously injected Evans blue into the gastric mucosa was used as an indicator of vascular permeability. Monastral blue was used to demonstrate vascular injury morphologically. The extravasated content of Evans blue significantly increased and reached the maximum at 2 h after indomethacin administration. The increase in Evans blue content was significantly inhibited by the pretreatment with superoxide dismutase (SOD) and SOD + catalase, but not with catalase alone. Monastral blue-labeled damaged endothelial cells in the gastric mucosa also increased at 2 h after indomethacin administration, which increase was reduced by pretreatment with SOD and SOD + catalase. These results indicate that oxygen radicals, including the superoxide radical, play an important role in the microvascular injury induced by indomethacin, which in turn plays a primary role in the development of gross hemorrhagic erosions.