Pentoxifylline (PF) has been shown to increase tissue oxygen tension. This study was performed to determine if PF has a protective effect on the gastric mucosa against alcohol (EtOH)-induced injury. Fasted Sprague-Dawley rats were pretreated with randomized test solution (control, normal saline, or PF, 75 mg/kg) intraperitoneally (ip). At 30 min, 100% EtOH (pH 8.5) was given intragastric. At 90 min, laparotomy was performed and gastric serosal stomach surface oxygen tensions (pO2) were measured. Stomachs were excised and opened and pH was measured. Photographs were taken and sections were obtained for histologic analysis to determine mucosal injury. The PF-pretreated rats had significantly higher serosal pO2 and significantly lower intragastric pH than control animals. There was significantly less gross and histologic mucosal injury in PF-treated animals. We conclude that PF is protective against EtOH gastric mucosal injury. This effect correlates with increased gastric serosal pO2 and is likely due to improved microcirculatory blood flow following PF administration.