OBJECTIVE To determine the effects of pretreatment and posttreatment with pentoxifylline in a porcine model of gram-negative sepsis. METHODS Nonrandomized controlled trial. METHODS Young Yorkshire swine. METHODS Six groups of ventilated swine were studied for 5 hours. Group 1 swine (control, n = 8) received saline solution only. Group 2 swine (sepsis, n = 8) received a 1-hour infusion of Pseudomonas aeruginosa. Groups 3, 4, and 5 swine received the P aeruginosa infusion and a 20 mg/kg bolus followed by a 6 mg/kg per hour infusion of pentoxifylline. Group 3 swine (n = 6) received pentoxifylline prior to the onset of sepsis; group 4 swine (n = 6) received pentoxifylline at 1 hour and group 5 swine (n = 4) at 2 hours after the onset of the P aeruginosa infusion. Group 6 swine (control pentoxifylline, n = 3) received pentoxifylline only. METHODS Hemodynamic variables, neutrophil counts and CD18 expression, tumor necrosis factor activity, and arterial blood gases were measured hourly. Bronchoalveolar lavage was performed at 0 and 5 hours to measure neutrophil and protein content. RESULTS All variables remained unchanged in the control and control pentoxifylline groups. Both pretreatment and posttreatment with pentoxifylline significantly attenuated lung injury and improved arterial PaO2. The cardiac index was significantly improved by administration of pentoxifylline in groups 3 and 4. Administration of pentoxifylline to group 5 animals in established septic shock caused uncontrolled, fatal systemic hypotension in two of the four animals. Plasma tumor necrosis factor activity, blood polymorphonuclear leukocyte counts, and CD18 expression were unaffected by the administration of pentoxifylline. CONCLUSIONS Pentoxifylline protects against pulmonary and systemic hemodynamic derangements in fulminant sepsis and protects against pulmonary dysfunction. Pentoxifylline has a "therapeutic window" when given in established sepsis; if administration is delayed until overt septic shock occurs, it may then have deleterious effects.