OBJECTIVE: To determine if treatment with pentoxifylline would decrease the tissue injury that occurs in a normotensive model of sepsis. DESIGN: Random assignment to control, cecal ligation-perforation, or cecal ligation-perforation plus pentoxifylline groups for a 24-hr study. SETTING: Animal laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Sepsis was induced by cecal ligation-perforation with aggressive fluid resuscitation (normal saline 10 mL/kg/hr). Pentoxifylline was administered as a 2-mg/kg bolus, followed by a continuous infusion of 6 mg/kg/hr. MEASUREMENTS AND MAIN RESULTS: Compared with controls, rats in the cecal ligation-perforation group had an increased heart rate (432 +/- 12 vs. 399 +/- 10 beats/min) and respiratory rate (129 +/- 6 vs. 94 +/- 7 breaths/min). Blood pressure was slightly decreased (104 +/- 4 vs. 125 +/- 5 mm Hg), while cardiac index was not significantly different (50.1 +/- 5.7 vs. 40.7 +/- 3.9 mL/min/100 g). Blood pressure (103 +/- 4 mm Hg) was the only parameter that was significantly different in the cecal ligation-perforation plus pentoxifylline group compared with controls. When compared with controls, tissue wet/dry weight ratios were increased in the diaphragm of the cecal ligation-perforation group and in the liver, pancreas, small bowel, and large bowel of the cecal ligation-perforation, and the cecal ligation-perforation plus pentoxifylline groups. Tissue/plasma albumin ratios were increased in the diaphragm of the cecal ligation-perforation group and in the liver, pancreas, and large bowel of the cecal ligation-perforation and the cecal ligation-perforation plus pentoxifylline groups. There were no significant differences between the cecal ligation-perforation and the cecal ligation-perforation plus pentoxifylline groups. CONCLUSIONS: Normotensive sepsis is accompanied by increased vascular permeability in the diaphragm and intra-abdominal organs. Pentoxifylline appears to attenuate some of the systemic manifestations of sepsis. However, pentoxifylline did not prevent the development of protein-rich tissue edema.