We have previously documented that a nonlethal dose of zymosan causes gut mucosal injury associated with increased xanthine oxidase activity and bacterial translocation. The current study was performed to investigate the role of xanthine oxidase activation and other potential mediators of intestinal injury in an LD50 zymosan model. Specific pathogen-free rats and mice were pretreated with saline, allopurinol, or ibuprofen prior to intraperitoneal injection of either saline or the LD50 dose of zymosan. Bacterial translocation to the mesenteric lymph node and systemic organs was measured at 6 or 24 hr following injection. In addition, separate animals in each group were followed for 7 days for survival. Pretreatment with allopurinol or ibuprofen reduced both the incidence and the magnitude of translocation at 6 hr in rats and mice (P < 0.05). In the rats pretreated with allopurinol or ibuprofen, no reduction in the incidence or magnitude of translocation occurred at 24 hr. In the mice pretreated with allopurinol or ibuprofen, although the incidence of translocation was not reduced at 24 hr, the magnitude of translocation was reduced (P < 0.05). Pretreatment with allopurinol or ibuprofen also resulted in an improvement in survival, when compared to zymosan alone (P < 0.01). Allopurinol and ibuprofen provide protection against bacterial translocation and improvement in survival following challenge with a lethal dose of zymosan.