Objective: To determine the influence of pentoxifylline on endothelial-associated coagulation. Design: prospective, randomized, placebo controlled study. Setting: A surgical intensive care unit of a university hospital. Patients: Consecutive patients (n = 60) with trauma sepsis secondary to major (nontrauma) surgery. All patients received controlled mechanical ventilation. Interventions: According to a randomized sequence, the patients either received pentoxifylline continuously over 5 days (1.5 mg/kg/hr iv) (trauma-pentoxifylline group [n = 15], sepsis-pentoxifylline group [n = 15]) or saline solution as placebo (trauma-control group [n = 15], sepsis-control group [ n = 15]). Measurements and Main Results: In addition to the standard coagulation screen, thrombomodulin, protein C, (free) protein S: and thrombin-antithrombin plasma concentrations were measured by enzyme-linked immunosorbent: assays. Intensive care therapy, hemodynamics, and changes of Acute Physiology and Chronic Health Evaluation II score were comparable for pentoxifylline-treated and nontreated patients. An average dose of 2.5 g/day of pentoxifylline (range 2.2 to 2.9) was infused into the pentoxifylline treated patients. At baseline, plasma thrombomodulin concentrations were higher in the septic patients than in the trauma patients. Thrombomodulin plasma concentrations increased significantly more in the control patients(trauma: from 38.9 +/- 10.5 to 59.9 +/- 10.1 ng/mL; sepsis: from 49.7 +/- 12.1 to 72.3 +/- 11.2 ng/mL) than in the pentoxifylline-treated patients (trauma: from 37.9 +/- 11.9 to 50.2 +/- 9.2 ng/mL; sepsis: from 51.9 +/- 10.1 to 63.3 +/- 10.2). Starting from similar baseline values, protein C concentration increased significantly more in the sepsis pentoxifylline patients (from 52.0 +/- 11.1% to 69.1 +/- 11.1%) than in the untreated septic patients (from 50.1 +/- 10.0% to 52.5 +/- 9.5%). There were no significant differences between the pentoxifylline-treated and nontreated groups for protein S and thrombin-antithrombin concentrations. Standard coagulation parameters (fibrinogen, activated partial thromboplastin time, antithrombin III) did not differ between these groups either. Conclusions: Continuous intravenous administration of pentoxifylline far 5 days beneficially influenced the thrombomodulin/protein C/protein S system in both the trauma and septic patients.