Several factors, including uncontrolled inflammation, gut barrier failure, and sepsis, have been implicated in the development of multiple organ failure. To investigate the relative importance and interrelationships among some of these factors, increasing doses of the inflammatory agent zymosan were used to induce a systemic inflammatory state in mice. At nonlethal doses (0.1 and 0.5 mg/g body weight), zymosan caused injury to the intestinal mucosa, increased intestinal xanthine oxidase activity, and promoted bacterial translocation in a dose-dependent fashion. Inhibition or inactivation of xanthine oxidase activity was effective in reducing mucosal injury and bacterial translocation when zymosan was injected at 0.1 mg/g but not at 0.5 mg/g body weight. At a dose of 1 mg/g, the lethal effects of zymosan appeared to be related to gut-origin sepsis, since cefoxitin (1 mg/g) reduced the seven-day mortality rate from 100% to 20% (p less than 0.01). However, at a zymosan dose of 2 mg/g, antibiotics did not improve survival. Zymosan thus induced gut barrier failure and systemic infection in a dose-dependent fashion. Additionally, the mechanism of zymosan-induced bacterial translocation and the relationship of gut-origin sepsis to survival appeared to be related to the magnitude of the inflammatory insult (the dose of zymosan).